Venclexta

/ AbbVie

Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to reduce risk of TLS.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
All VENCLEXTA dose regimens begin with a 5-week ramp-up.
VENCLEXTA 5-week Dose Ramp-Up Schedule: Administer the VENCLEXTA dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1 at the attached doctor’s leaflet. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.
The CLL/SLL Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule. The 400 mg dose is achieved using 100 mg tablets supplied in bottles.
VENCLEXTA in Combination with Rituximab: Start rituximab administration after the patient has completed the 5-week dose ramp-up schedule with VENCLEXTA (see Table 1) and has received the 400 mg dose of VENCLEXTA for 7 days. Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, with rituximab dosed at 375 mg/m² intravenously for Cycle 1 and 500 mg/m²
intravenously for Cycles 2-6.
Patients should continue VENCLEXTA 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab.
VENCLEXTA as Monotherapy: The recommended dose of VENCLEXTA is 400 mg once daily after the patient has completed the 5-week dose ramp-up schedule. VENCLEXTA should be taken orally once daily until disease progression or unacceptable toxicity is observed.
Acute Myeloid Leukemia
The dose of VENCLEXTA depends upon the combination agent.
The VENCLEXTA dosing schedule (including ramp-up) is shown in Table 2 at the attached doctor’s leaflet. Initiate the azacitidine or decitabine or low-dose cytarabine on Day 1.
Continue VENCLEXTA, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity is observed.
Missed Dose: If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the next day.
If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time.
See prescribing information for full details.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: VENCLEXTA is indicated for the treatment of: patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.
Acute Myeloid Leukemia: VENCLEXTA in combination with a hypomethylating agent or in combination with low dose cytarabine is indicated for newly diagnosed patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during the rampup phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome.
Concomitant use of preparations containing St. John’s wort.
Hypersensitivity to venetoclax, or to any of the excipients within the formulation.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients with high tumor burden when treated with VENCLEXTA.
Neutropenia: In patients with CLL, Grade 3 or 4 neutropenia developed in 64% of patients and Grade 4 neutropenia developed in 31% of patients treated with VENCLEXTA in combination with rituximab (see Table 10 at the attached doctor’s leaflet). Grade 3 or 4 neutropenia developed in 63% of patients and Grade 4 neutropenia developed in 33% of patients treated with VENCLEXTA monotherapy (see Table 12 at the attached doctor’s leaflet). Febrile neutropenia occurred in 4% of patients treated with VENCLEXTA in combination with rituximab and in 6% of patients treated with VENCLEXTA monotherapy.
Baseline neutrophil counts worsened in 97% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles of therapy.
Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of 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 closely for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and higher infection.
Immunization: Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations may be less effective.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, VENCLEXTA may cause embryofetal harm when administered to a pregnant woman.
See prescribing information for full details.

Tumor Lysis Syndrome, Neutropenia.
See prescribing information for full details.

Effects of Other Drugs on VENCLEXTA
Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors: Concomitant use of Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax Cmax and AUCinf, which may increase VENCLEXTA toxicities, including the risk of TLS.
Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated.
In patients with CLL/SLL taking a steady daily dosage (after ramp-up phase), consider alternative medications or adjust VENCLEXTA dosage and closely monitor for signs of VENCLEXTA toxicities.
In patients with AML, adjust VENCLEXTA dosage and closely monitor for signs of
VENCLEXTA toxicities.
Resume the VENCLEXTA dosage that was used prior to concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.
Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A.
Moderate CYP3A Inhibitors and P-gp Inhibitors: Avoid concomitant use of moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil) or P-gp inhibitors (e.g., amiodarone, captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine, ticagrelor) with VENCLEXTA. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the VENCLEXTA dose by at least 50%. Monitor patients more closely for signs of VENCLEXTA toxicities.
Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor.
Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A.
Co-administration of a single dose of rifampin, a P-gp inhibitor, increased venetoclax Cmax by 106% and AUC∞ by 78%.
Strong or Moderate CYP3A Inducers: Concomitant use with a strong CYP3A inducer decreases venetoclax Cmax and AUCinf, which may decrease VENCLEXTA efficacy. Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers. Preparations containing St. John’s wort are contraindicated during treatment with venetoclax, as efficacy may be reduced.
Effects of VENCLEXTA on Other Drugs
Warfarin: Concomitant use of VENCLEXTA increases warfarin Cmax and AUCinf, which may increase the risk of bleeding. Closely monitor international normalized ratio (INR) in patients using warfarin concomitantly with VENCLEXTA.
P-gp Substrates: Concomitant use of VENCLEXTA increases Cmax and AUCinf of P-gp substrates, which may increase toxicities of these substrates. Avoid concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.

Pregnancy: There are no available data on VENCLEXTA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Based on toxicity observed in mice, VENCLEXTA may cause fetal harm when administered to pregnant women. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while taking VENCLEXTA, the patient should be apprised of the potential risk to a fetus.
Lactation: There are no data on the presence of VENCLEXTA in human milk, the effects of VENCLEXTA on the breastfed child, or the effects of VENCLEXTA on milk production. Venetoclax was present in the milk when administered to lactating rats.
Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from VENCLEXTA is unknown, advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA.
See prescribing information for full details.

There is no specific antidote for VENCLEXTA. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities. Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.