Initiation: Dosing and drug interactions

Dose ramp-up is designed to allow patients to safely attain the recommended daily dose1

  • 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 (venetoclax tablets) to reduce risk of TLS
  • Instruct patients to take VENCLEXTA tablets with a meal and water at approximately the same time each day. VENCLEXTA tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing

Pretreatment TLS risk assessment and prophylaxis1

  • 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 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, consider additional measures, including increased laboratory monitoring and reducing VENCLEXTA starting dose

TLS in clinical trials1,7

  • With implementation of dosing ramp-up plus standard TLS prophylaxis and monitoring:
    • In VIALE-A, the rate of TLS was 1.1% (3/283) in patients who received VENCLEXTA in combination with azacitidine. All events were laboratory TLS
    • In VIALE-C, the rate of TLS was 5.6% (8/142) in patients who received VENCLEXTA in combination with low-dose cytarabine. There were 4 events of laboratory TLS and 4 events of clinical TLS, which included 2 deaths and cases of renal failure

Dosing schedule for VENCLEXTA + azacitidine (AZA)1

In the VIALE-A trial, which evaluated the efficacy and safety of VEN+AZA:

  • Azacitidine was administered in 28-day cycles, beginning on Day 1 of VENCLEXTA treatment, at a dosage of 75 mg/m2, intravenously or subcutaneously once daily on Days 1-7 of each cycle
Chart of the daily dosing schedule and ramp-up for patients taking VENCLEXTA combined with azacitidine. Initiate patients with one VENCLEXTA 100 mg pill on day 1, two VENCLEXTA 100 mg pills on day 2, and four 100 mg VENCLEXTA pills on day 3 and beyond. Azacitidine was administered in 28-day cycles, beginning on Day 1 of VENCLEXTA treatment, at a dosage of 75 mg/m2, IV or SC, on Days 1-7 of each cycle. Continue treatment until disease progression or unacceptable toxicity.

Dosing schedule for VENCLEXTA + decitabine (DEC) or low-dose cytarabine (LDAC)1

  • If using VENCLEXTA in combination with decitabine, follow the dose ramp-up schedule for VENCLEXTA 400 mg and administer decitabine at 20 mg/m2 intravenously once daily on Days 1-5 of each 28-day cycle beginning on Cycle 1, Day 1
  • If using VENCLEXTA in combination with low-dose cytarabine, follow the dose ramp-up schedule for VENCLEXTA 600 mg and administer cytarabine at 20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle beginning on Cycle 1, Day 1. For more information, please refer to the full Prescribing Information

VENCLEXTA dose should be modified for concomitant use with certain medications1,8,9

  • VENCLEXTA is metabolized by the CYP3A enzyme; the dose should be reduced when used with P-gp inhibitors or strong or moderate CYP3A inhibitors
Dose modifications for managing potential interactions
Coadministered drug
Initiation and ramp-up phase Steady daily dose after
ramp-up phase
Posaconazole Day 1: 10 mg
Day 2: 20 mg
Day 3: 50 mg
Day 4: 70 mg
Reduce the VENCLEXTA dose
to 70 mg
Other strong CYP3A inhibitor Day 1: 10 mg
Day 2: 20 mg
Day 3: 50 mg
Day 4: 100 mg
Reduce the VENCLEXTA dose
to 100 mg
Moderate CYP3A inhibitor Reduce the VENCLEXTA dose by at least 50%
P-gp inhibitor
Examples of other coadministered CYP3A and P-gp inhibitors
Other strong CYP3A inhibitors Clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, telaprevir, voriconazole*
Moderate CYP3A inhibitors Aprepitant, ciprofloxacin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, isavuconazole, verapamil*
P-gp inhibitors Amiodarone, carvedilol, clarithromycin, cyclosporine, dronedarone, itraconazole, ketoconazole, quinidine, ranolazine, ritonavir, verapamil*
  • Adjust the VENCLEXTA dose and monitor more frequently for adverse reactions. 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 inhibitor1
  • Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A1
  • Concomitant use of VENCLEXTA with strong CYP3A inducers decreases VENCLEXTA exposure, which may decrease VENCLEXTA efficacy. Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers1
  • Concomitant use of VENCLEXTA increases warfarin exposure, which may increase the risk of bleeding. Monitor international normalized ratio (INR) more frequently in patients using warfarin concomitantly with VENCLEXTA1
  • Concomitant use of VENCLEXTA increases exposure of P-gp substrates, which may increase toxicities of these substrates. Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA1

Dose modifications for patients with severe hepatic impairment1

  • 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

*This is not an exhaustive list and is intended only to complement, not replace, clinical judgment during treatment of patients with VENCLEXTA. Please refer to the FDA website for more examples.

CYP3A=cytochrome P450 3A; P-gp=P-glycoprotein.
CRESEMBA® is a registered trademark of Astellas US LLC.

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Efficacy

Review study design, overall survival data, remission rates, and more

Safety Data

Review adverse reactions, duration of exposure, and discontinuation rates

Dosing/Management

Review appropriate dosing and management of select adverse reactions

Indication

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

Tumor Lysis Syndrome

  • Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA.
  • 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. 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.
  • 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. 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.
  • The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy.
  • 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 (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA follow dose modification guidance in the Prescribing Information.
  • 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, and requires VENCLEXTA dose reduction.

Neutropenia

  • In patients with AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles.
  • Monitor complete blood counts. Interrupt dosing for severe neutropenia. Resume at same dose then reduce duration based on remission status and first or subsequent occurrence of neutropenia. 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. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution and resume at same dose.

Immunization

  • Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective. 

Embryo-Fetal Toxicity

  • VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose.

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. 

Adverse Reactions

  • In patients with AML receiving combination therapy with azacitidine, the most frequent serious adverse reactions (≥5%) were febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were neutrophils decreased (98%), platelets decreased (94%), lymphocytes decreased (91%), hemoglobin decreased (61%), nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with azacitidine, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%).
  • In patients with AML receiving combination therapy with decitabine, the most frequent serious adverse reactions (≥10%) were sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were neutrophils decreased (100%), lymphocytes decreased (100%), white blood cells decreased (100%), platelets decreased (92%), hemoglobin decreased (69%), 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%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment.
  • In patients with AML receiving combination therapy with low-dose cytarabine, the most frequent serious adverse reactions (≥10%) were pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were platelets decreased (97%), neutrophils decreased (95%), lymphocytes decreased (92%), hemoglobin decreased (63%), nausea (42%), and febrile neutropenia (32%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%).

Drug Interactions

  • Concomitant use with a P-gp inhibitor or a strong or moderate CYP3A inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions. Resume the VENCLEXTA dosage that was used prior to concomitant use of a P-gp inhibitor or a strong or moderate CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.
  • Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A. 
  • Avoid concomitant use of strong or moderate CYP3A inducers.  
  • Monitor international normalized ratio (INR) more frequently in patients receiving warfarin.
  • Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA. 

Lactation

  • Advise nursing women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.

Females and Males of Reproductive Potential

  • Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose.
  • Based on findings in animals, VENCLEXTA may impair male fertility.

Hepatic Impairment 

  • Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for signs of adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Please see full Prescribing Information.

VENCLEXTA®, VENCOMPASS® and their designs are registered trademarks of AbbVie Inc.

    • VENCLEXTA Prescribing Information.

      VENCLEXTA Prescribing Information.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed March 2, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed March 2, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

    • DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.

      DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.

    • Data on file, AbbVie Inc. ABVRRTI71211.

      Data on file, AbbVie Inc. ABVRRTI71211.

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      Data on file, AbbVie Inc. ABVRRTI67697.

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      Data on file, AbbVie Inc. ABVRRTI71500.

    • CRESEMBA Prescribing Information.

      CRESEMBA Prescribing Information.

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      Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. Updated March 6, 2020. Accessed October 15, 2020.

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