INITIATING VENCLEXTA1
When you’re ready to start VENCLEXTA, here is information to help you assess, prep, and initiate your patients. VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for tumor lysis syndrome (TLS). The 3-step initiation protocol is designed to help reduce the risk of TLS.
TUMOR BURDEN
Perform tumor burden assessment, including radiographic evaluation (eg, CT scan). The risk of TLS may decrease as tumor burden decreases.
TUMOR BURDEN
| LOW | MEDIUM | HIGH | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
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BLOOD CHEMISTRY ASSESSMENT
Assess blood chemistry and correct preexisting abnormalities prior to initiation of treatment.
- Potassium
- Phosphorus
- Creatinine
- Uric acid
- Calcium
MEDICATION RECONCILIATION
Determine if your patient is currently taking any of the following, which may require VENCLEXTA dose modifications:
- Posaconazole or other strong CYP3A inhibitor
- Moderate CYP3A inhibitor
- P-gp inhibitor
ADDITIONAL CONSIDERATIONS
Consider all patient comorbidities before final determination of prophylaxis and monitoring schedule.
- Renal function
- Splenomegaly
- Other patient comorbidities
ALC=absolute lymphocyte count; CT=computed tomography; CYP3A=cytochrome P450 3A; LN=lymph node; P-gp=P-glycoprotein.
At least 2 days prior to the first dose:
HYDRATION
TUMOR BURDEN
| LOW | MEDIUM | HIGH | |||||||
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ANTI-HYPERURICEMICS
TUMOR BURDEN
| LOW | MEDIUM | HIGH | ||||||
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*1.5 to 2 L (~56 oz) of water should be consumed every day starting at least 2 days before the first dose and throughout the dose escalation phase, especially the first day of each dose increase. Administer IV hydration for any patient who cannot tolerate oral hydration.
†Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA.
IV=intravenous.
Monitor blood chemistry*† for first dose of each ramp-up week.
LOW Tumor Burden OR MEDIUM Tumor Burden
LOW Tumor Burden
ORMEDIUM Tumor Burden
OUTPATIENT
DAY 1, WEEK
1
2
3
4
5
Dosage
20 mg
50 mg
100 mg
200 mg
400 mg
Blood chemistry labs
Pre-dose
6 to 8 hrs
24 hrs
For the first doses of 20 mg and 50 mg, consider hospitalization for patients with medium tumor burden and CrCl <80 mL/min; for these patients, see table on the right for monitoring in hospital.
HIGH Tumor Burden
HIGH Tumor Burden
HOSPITAL
OUTPATIENT
DAY 1, WEEK
1
2
3
4
5
Dosage
20 mg
50 mg
100 mg
200 mg
400 mg
Blood chemistry labs
Pre-dose
4 hrs
8 hrs
12 hrs
24 hrs
*Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.
†For patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent dose escalation.
CrCl=creatinine clearance.
Indications
VENCLEXTA is indicated:
- For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
- 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
Contraindication
- Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome (TLS).
Tumor Lysis Syndrome
- Tumor lysis syndrome, 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, and during reinitiation after dosage interruption in patients with CLL/SLL. 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.
- In patients with CLL/SLL 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/SLL 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/SLL, the TLS rate was 13% and included deaths and renal failure.
- 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. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL.
- 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 CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients treated with VENCLEXTA in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients.
- 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. In CLL, resume at same or reduced dose. In AML, 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 or reduced 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 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 CLL receiving combination therapy with obinutuzumab, serious adverse reactions were most often due to febrile neutropenia and pneumonia (5% each). The most common adverse reactions (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). 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 patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (≥5%) was pneumonia (9%). The most common adverse reactions (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). 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 the last rituximab were reported in 2% (4/194) of patients.
- In patients with CLL/SLL receiving monotherapy, the most frequent serious adverse reactions (≥5%) were pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). The most common adverse reactions (≥20%) of any grade were neutropenia (50%), diarrhea (43%), nausea (42%), upper respiratory tract infection (36%), anemia (33%), fatigue (32%), thrombocytopenia (29%), musculoskeletal pain (29%), edema (22%), and cough (22%). 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.
- 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 adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
US-VEN-220038
Please see full Prescribing Information.
VENCLEXTA® and its design are registered trademarks of AbbVie Inc.
References: 1. VENCLEXTA Prescribing Information. 2. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23)(suppl):2225-2236.