22

September

Venetoclax (Venclexta®) Risk Stratification, Dosing, and Dispensing Procedure

Written By: Jon Suyko, PharmD, BCPS UCHealth Highlands Ranch
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Description: Venetoclax therapy requires particular parameters be closely followed to ensure optimal patient outcomes. This PQI will review appropriate risk stratification, dosing, and dispensing procedures.  These risk stratifications create special challenges for the dispensing of venetoclax. Some medium-risk and all high-risk patients may require hospital admission during titration; communication between the oncology pharmacist, nurse, lab technicians, hematologist, and the patient will ensure the recommended administration guidelines and lab monitoring are followed to ensure patient safety and best outcomes.

Background: Venetoclax is indicated in Acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL) and small lymphocytic leukemia (SLL) in patients with or without chromosome 17p deletion. During the ramp-up phase, patients are titrated on venetoclax and assigned a risk category based on tumor burden and potential for developing Tumor Lysis Syndrome (TLS). TLS can occur when there is large tumor burden (large size of any lymph node, or, elevated Absolute Lymphocyte Count (ALC). In patients with CLL treated with single-agent venetoclax, the rate of TLS was 2%. The rate remained consistent for venetoclax in combination with obinutuzumab or rituximab. In patients with AML, the incidence of TLS was 5.6% in combination treatment with cytarabine. Patients at high risk for TLS should be admitted for initiation of venetoclax. Labs that should be monitored according to the manufacturers’ guidelines include serum creatinine, uric acid, potassium, phosphorus and calcium. TLS is considered an oncologic emergency.

PQI Process: Upon receipt of a new prescription for venetoclax:

  • Determine if the prescriber has assigned a TLS risk category for the patient (see supplemental information)
  • If patient falls into the high TLS risk category (or medium risk with CrCl<80 mL/min), coordinate with the prescriber and patient the date and time of admission to the hospital
    • Ensure patient will have medication on hand prior to admission
  • CLL/SLL Patients
    • Coordinate with inpatient team timing of necessary lab work (see supplemental information)
    • Labs will need to be ordered for the first dose of 20 mg and 50 mg doses
      • This will occur on two separate admissions
    • Labs need to be drawn pre-dose, 4, 8, 12 and 24 hours after the dose
      • The recommended labs to monitor for TLS are uric acid, serum potassium, serum phosphorus, corrected calcium and serum creatinine
      • Ensure inpatient staff is aware of the lab orders and the frequency so the labs are not seen as “duplicates” and inadvertently cancelled
      • Labs need to be reviewed in “real time” for early detection of TLS
    • AML Patients
      • For patients with risk factors for TLS additional measures should be considered, including increased laboratory monitoring and reducing starting dose
      • 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
  • All AML patients should have a WBC < 25 x 109/L prior to initiation of venetoclax
    • Cytoreduction prior to treatment may be required
    • Hospital admission for TLS monitoring should be assessed case by case
  • In select patients, rasburicase may be used for TLS management
  • Dosing Guideline: For all indications assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose and throughout the ramp-up phase to reduce risk of TLS

Venetoclax Ramp-Up Schedule

CLL/SLL§AML§ The CLL/SLL Starting Pack provides the first 4 weeks of venetoclax according to the ramp-up schedule. The 400 mg dose is achieved using 4 x 100 mg tablets supplied in bottles

 

*400 mg when used in combination with azacitidine or decitabine; 600 mg when used in combination with low dose cytarabine

Week 120 mgDay 1100 mg
Week 250 mg

 

Day 2200 mg
Week 3100 mgDay 3400 mg
Week 4200 mgDay 4 and beyond400 mg or

600 mg*

Week 5 and beyond400 mg 

 

Patient Centered Activities:

  • Provide Oncology Chemotherapy Education (OCE) sheet
  • Review titration schedule with patient
  • Confirm if patient has allopurinol prescribed
    • Review that allopurinol should be initiated 2-3 days prior to venetoclax
  • Review oral hydration schedule with patient
    • Patient should consume 6 – 8 (8 oz) glasses of water or as instructed by their provider daily starting 2 days before the first dose and throughout the ramp up phase *This is important during the first day of each dose increase*
    • Patients admitted to the hospital will receive IV fluids
    • Outpatients may be considered for IV hydration if oral hydration is inadequate
  • For a missed dose:
    • If within 8 hours of the usual time, take as soon as possible and resume normal schedule
    • If greater than 8 hours past the usual time, skip and resume normal schedule the next day
  • Confirm with the patient the date, time, and location of hospital if admission is necessary
  • Consider providing a calendar with dosing schedule and lab appointments
  • Follow up with patient after each dose escalation to confirm patient is taking medications properly

Supplemental Information:

Table 1: Recommended TLS Prophylaxis Based on Tumor Burden in Patients with CLL/SLL

Tumor Burden ClassificationAnti-hyperuricemicsHydrationLab Monitoring
Low Tumor Burden
All lymph nodes

<5 cm and

ALC <25×109/L

Allopurinol

Start 2-3 days prior to first dose

Oral (1.5-2 L/day) beginning 2-3 days prior to first doseOutpatient: First dose of 20 mg and 50 mg: Pre-dose, 6-8 hrs and 24 hrs

Subsequent ramp up doses: Pre-dose only

Medium Tumor Burden
Any lymph node 5cm to <10 cm or ALC> = 25 x 109/LAllopurinol

Start 2-3 days prior to first dose

Oral (1.5-2L/day) beginning 2-3 days prior to first dose

Consider additional IV if in hospital

Outpatient: First dose of 20 mg and 50 mg: Pre-dose, 6-8 hrs and 24 hrs Subsequent ramp up doses: Pre-dose only If CrCl<80 ml/min consider hospitalization and follow lab monitoring for inpatient below
High Tumor Burden
Any lymph node >= 10cm or

Any lymph node >= 5 cm

and ALC> = 25x 109/L

Allopurinol

Start 2-3 days prior to first dose

 

Consider rasburicase if elevated baseline uric acid

Check with inpatient pharmacy

for availability

Oral (1.5-2 L/day) beginning 2-3 days prior to first dose and IV (150- 200 mL/hr as tolerated)In hospital: For first dose of 20 mg and 50 mg: Pre-dose, 4 ,8 ,12 and 24 hrs

 

Outpatient:

For subsequent ramp-up doses: Pre-dose, 6-8 hrs and 24 hrs

 

Important Drug safety information:

  • Strong CYP3A – contraindicated during ramp up phase in CLL/SLL due to increased risk of TLS
  • Avoid grapefruit products, Seville oranges, and starfruit (all CYP3A inhibitors)
  • If a strong CYP3A inhibitor must be used, patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax reduce venetoclax by at least 75%.
    • Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor 2-3 days after discontinuation of the inhibitor
  • If a moderate CYP3A inhibitors or P-gp inhibitor must be used, reduce the venetoclax dose by at least 50%. Monitor patients more closely for signs of venetoclax Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.

References:

  1. VENCLEXTA® (Venetoclax) [Prescribing Information]. Chicago, IL: AbbVie, Inc.,
  2. Larson, R MD and Pui, Ching-Hon MD (2018). Tumor lysis syndrome: Prevention and treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate https://www.uptodate.com/contents/tumor-lysis-syndrome-prevention-and-treatment.
  3. Gold Standard, Inc. Monograph Name. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible  uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform   and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with  respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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