b'DO NOT RE-SIZEDO NOT RE-SIZE Ad unit Project # must match this project # 000-000000US-VENC-21030958 VENCLEXTA (venetoclax tablets) PROFESSIONAL BRIEF SUMMARYConsult Package Insert for full Prescribing InformationINDICATIONS AND USAGE In a randomized trial (BELLINI; NCT02755597) in patients with relapsedTable 2. New or Worsening Clinically Important Laboratory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or refractory multiple myeloma, the addition of VENCLEXTA to bortezomibAbnormalities (10%) in Patients Treated with VEN+G in CLL14VENCLEXTA is indicated for the treatment of adult patients with chronicplus dexamethasone, a use for which VENCLEXTA is not indicated, resulted lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). in increased mortality. Treatment of patients with multiple myeloma withVENCLEXTA +Obinutuzumab + VENCLEXTA in combination with bortezomib plus dexamethasone is notObinutuzumab ChlorambucilAcute Myeloid Leukemia recommended outside of controlled clinical trials. a (N = 212) (N = 214)VENCLEXTA is indicated in combination with azacitidine, or decitabine, orADVERSE REACTIONS Laboratory Abnormality AllGradeAllGrade low-dose cytarabine for the treatment of newly diagnosed acute myeloidThe following clinically significant adverse reactions are describedGrades3 or 4Grades3 or 4 leukemia (AML) in adults 75 years or older, or who have comorbidities thatelsewhere in the labeling:(%) (%) (%) (%)preclude use of intensive induction chemotherapy.Tumor Lysis Syndrome [see Warnings and Precautions] HematologyCONTRAINDICATIONSNeutropenia [see Warnings and Precautions]Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation Leukopenia 90 46 89 41and during the ramp-up phase is contraindicated in patients withInfections [see Warnings and Precautions]CLL/SLL due to the potential for increased risk of tumor lysis syndromeClinical Trials Experience Lymphopenia 87 57 87 51[see Drug Interactions].Because clinical trials are conducted under widely variable conditions, Neutropenia 83 63 79 56WARNINGS AND PRECAUTIONS adverse event rates observed in clinical trials of a drug cannot be directly Thrombocytopenia 68 28 71 26Tumor Lysis Syndrome compared with rates of clinical trials of another drug and may not reflect Tumor lysis syndrome (TLS), including fatal events and renal failurethe rates observed in practice. Anemia 53 15 46 11requiring dialysis, has occurred in patients treated with VENCLEXTA [seeIn CLL/SLL, the safety population reflects exposure to VENCLEXTA asChemistryAdverse Reactions].monotherapy in patients in M13-982, M14-032, and M12-175 and in VENCLEXTA can cause rapid reduction in tumor and thus poses a risk forcombination with obinutuzumab or rituximab in patients in CLL14 and Blood creatinine increased 80 6 74 2TLS at initiation and during the ramp-up phase in all patients, and duringMURANO. In this CLL/SLL safety population, the most common adverse Hypocalcemia 67 9 58 4reinitiation after dosage interruption in patients with CLL/SLL. Changes inreactions (20%) for VENCLEXTA were neutropenia, thrombocytopenia, blood chemistries consistent with TLS that require prompt managementanemia, diarrhea, nausea, upper respiratory tract infection, cough, Hyperkalemia 41 4 35 3can occur as early as 6 to 8 hours following the first dose of VENCLEXTAmusculoskeletal pain, fatigue, and edema. Hyperuricemia 38 38 38 38and at each dose increase. TLS, including fatal cases, has been reportedIn AML, the safety population reflects exposure to VENCLEXTA inaafter a single 20 mg dose of VENCLEXTA. combination with decitabine, azacitidine, or low-dose cytarabine inIncludes laboratory abnormalities that were new or worsening, or with In patients with CLL/SLL who followed the current (5-week) dose ramp-uppatients in M14-358, VIALE-A, and VIALE-C. In this safety population,worsening from baseline unknown. and the TLS prophylaxis and monitoring measures, the rate of TLS wasthe most common adverse reactions (30% in any trial) were nausea,Grade 4 laboratory abnormalities that developed in 2% of patients treated 2% in the VENCLEXTA CLL/SLL monotherapy trials. The rate of TLSdiarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia,with VEN+G included neutropenia (32%), leukopenia and lymphopenia remained consistent with VENCLEXTA in combination with obinutuzumabfatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage,(10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), or rituximab. With a 2- to 3-week dose ramp-up and higher starting doseanemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness,blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia in patients with CLL/SLL, the TLS rate was 13% and included deaths andcough, oropharyngeal pain, and hypotension. (2%). renal failure [see Adverse Reactions].Chronic Lymphocytic Leukemia/Small Lymphocytic LymphomaVENCLEXTA in Combination with Rituximab In patients with AML who followed the current 3-day ramp-up dosingVENCLEXTA in Combination with ObinutuzumabThe safety of VENCLEXTA in combination with rituximab (VEN+R) (N=194) schedule and the TLS prophylaxis and monitoring measures, the rate ofThe safety of VENCLEXTA in combination with obinutuzumab (VEN+G)versus bendamustine in combination with rituximab (B+R) (N=188) was TLS was 1.1% in patients who received VENCLEXTA in combination with(N=212) versus obinutuzumab in combination with chlorambucil (GClb)evaluated in MURANO. Patients randomized to VEN+R completed the azacitidine (VIALE-A). In patients with AML who followed a 4-day ramp-up(N=214) was evaluated in CLL14, a randomized, open-label, activelyscheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once dosing schedule and the TLS prophylaxis and monitoring measures, thecontrolled trial in patients with previously untreated CLL. Patientsdaily, in combination with rituximab for 6 cycles followed by VENCLEXTA rate of TLS was 5.6% and included deaths and renal failure in patientsrandomized to the VEN+G arm were treated with VENCLEXTA andmonotherapy, for a total of 24 months after ramp-up. At the time of who received VENCLEXTA in combination with low-dose cytarabineobinutuzumab in combination for six cycles, then with VENCLEXTA asanalysis, the median duration of exposure to VENCLEXTA was 22 months (VIALE-C) [see Adverse Reactions]. monotherapy for an additional six cycles. Patients initiated the first doseand the median number of cycles of rituximab was 6 in the VEN+R arm. The risk of TLS is a continuum based on multiple factors, particularlyof the 5-week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and onceSerious adverse reactions were reported in 46% of patients in the VEN+R reduced renal function, tumor burden, and type of malignancy.completed, continued VENCLEXTA 400 mg orally once daily for a totalarm, with most frequent (5%) being pneumonia (9%). Fatal adverse Splenomegaly may also increase the risk of TLS in patients with CLL/SLL. of 12 cycles. The trial required a total Cumulative Illness Rating Scalereactions that occurred in the absence of disease progression and within Assess all patients for risk and provide appropriate prophylaxis for TLS,(CIRS) 6 or CLcr 70 mL/min, hepatic transaminases and total bilirubin30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab including hydration and anti-hyperuricemics. Monitor blood chemistries2 times upper limit of normal and excluded patients with any individualwere reported in 2% (4/194) of patients. and manage abnormalities promptly. Employ more intensive measuresorgan/system impairment score of 4 by CIRS except eye, ear, nose, andIn the VEN+R arm, adverse reactions led to treatment discontinuation (intravenous hydration, frequent monitoring, hospitalization) as overall riskthroat organ system. The median duration of exposure to VENCLEXTA wasin 16% of patients, dose reduction in 15%, and dose interruption in increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow10.5 months (range: 0 to 13.5 months) and the median number of cycles71%. Neutropenia and thrombocytopenia each led to discontinuation of dose modification guidance [see Dosage and Administration in the fullof obinutuzumab was 6 in the VEN+G arm. VENCLEXTA in 3% of patients. Neutropenia led to dose interruption of Prescribing Information].Serious adverse reactions were reported in 49% of patients in theVENCLEXTA in 46% of patients.Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderateVEN+G arm, most often due to febrile neutropenia and pneumonia (5%Table 3 presents adverse reactions identified in MURANO.CYP3A inhibitors increases venetoclax exposure, which may increase theeach). Fatal adverse reactions that occurred in the absence of disease risk of TLS at initiation and during the ramp-up phase of VENCLEXTA.progression and with onset within 28 days of the last study treatment wereTable 3. Adverse Reactions (10%) in Patients Treated with VEN+R For patients with CLL/SLL, coadministration of VENCLEXTA with strongreported in 2% (4/212) of patients, most often from infection.in MURANOCYP3A inhibitors at initiation and during the 5-week ramp-up phase isIn the VEN+G arm, adverse reactions led to treatment discontinuation inVENCLEXTA +Bendamustine + contraindicated [see Contraindications]. For patients with AML, reduce the16% of patients, dose reduction in 21%, and dose interruption in 74%.Rituximab (N = 194) Rituximab (N = 188)dose of VENCLEXTA when coadministered with strong CYP3A inhibitors atNeutropenia led to discontinuation of VENCLEXTA in 2% of patients, doseAdverse Reaction initiation and during the 3- or 4-day ramp-up phase. For patients with reduction in 13%, and dose interruption in 41%. All GradesGrade 3All GradesGrade 3 CLL/SLL or AML, reduce the dose of VENCLEXTA when coadministeredTable 1 presents adverse reactions identified in CLL14.(%) (%) (%) (%)with moderate CYP3A4 inhibitors or P-gp inhibitors [see Drug Interactions].Table 1. Adverse Reactions (10%) in Patients Treated with VEN+GBlood and lymphatic system disordersNeutropenia in CLL14 Neutropeniaa 65 62 50 44In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64%VENCLEXTA +Obinutuzumab +aof patients and Grade 4 neutropenia developed in 31% to 33% of patientsObinutuzumab Chlorambucil Anemia 16 11 23 14when treated with VENCLEXTA in combination and monotherapy studies.Adverse Reaction(N = 212) (N = 214) Gastrointestinal disordersFebrile neutropenia occurred in 4% to 6% of patients [see Adverse Reactions].All GradesGrade 3All GradesGrade 3Diarrhea 40 3 17 1In patients with AML, baseline neutrophil counts worsened in 95% to(%) (%) (%) (%) Nausea 21 1 34 1100% of patients treated with VENCLEXTA in combination with azacitidine,Blood and lymphatic system disordersdecitabine, or low-dose cytarabine. Neutropenia can recur with subsequentConstipation 14 1 21 0cycles. Neutropeniaa 60 56 62 52 Infections and infestationsMonitor complete blood counts throughout the treatment period. Consider Anemiaa 17 8 20 7supportive measures, including antimicrobials and growth factors (e.g.,Upper respiratory 39 2 23 2G-CSF).Gastrointestinal disorders tract infectionaInfectionsDiarrhea 28 4 15 1 Lower respiratory 18 2 10 2Fatal and serious infections, such as pneumonia and sepsis, have occurred Nausea 19 0 22 1 tract infectionain patients treated with VENCLEXTA [see Adverse Reactions].Pneumoniaa 10 7 14 10Monitor patients for signs and symptoms of infection and treat promptly. Constipation 13 0 9 0Withhold VENCLEXTA for Grade 3 and 4 infection until resolution. Vomiting 10 1 8 1 General disorders and administration site conditionsImmunization General disorders and administration site conditions Fatiguea 22 2 26 1Do not administer live attenuated vaccines prior to, during, or aftera aIncludes multiple adverse reaction terms. treatment with VENCLEXTA until B-cell recovery occurs. The safety Fatigue 21 2 23 1and efficacy of immunization with live attenuated vaccines during orInfections and infestations Other clinically important adverse reactions (All Grades) reported in 10% following VENCLEXTA therapy have not been studied. Advise patients thatof patients treated with VEN+R are presented below: vaccinations may be less effective. Upper respiratory Blood and lymphatic system disorders: febrile neutropenia (4%) Embryo-Fetal Toxicitytract infectiona 17 1 17 1 Gastrointestinal disorders: vomiting (8%) Based on findings in animals and its mechanism of action, VENCLEXTAaIncludes multiple adverse reaction terms.Infections and infestations: sepsis (1%) may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of venetoclaxOther clinically important adverse reactions (All Grades) reported in 10%Metabolism and nutrition disorders: tumor lysis syndrome (3%)to pregnant animals at exposures equivalent to that observed in patients atof patients treated with VEN+G are presented below:During treatment with VENCLEXTA monotherapy after completion of a dose of 400 mg daily resulted in post-implantation loss and decreasedBlood and lymphatic system disorders: febrile neutropenia (6%)VEN+R combination treatment, adverse reactions that occurred in 10% fetal weight.Infection and infestations (all include multiple adverse reaction terms):of patients were upper respiratory tract infection (21%), diarrhea (19%), Advise pregnant women of the potential risk to a fetus. Advise femalespneumonia (9%), urinary tract infection (6%), sepsis (4%)neutropenia (16%), and lower respiratory tract infections (11%). The Grade 3 or 4 adverse reactions that occurred in 2% of patients were of reproductive potential to use effective contraception during treatmentMetabolism and nutrition disorder: tumor lysis syndrome (1%)neutropenia (12%) and anemia (3%). with VENCLEXTA and for 30 days after the last dose [see Use in SpecificDuring treatment with VENCLEXTA monotherapy after completion ofTable 4 presents laboratory abnormalities identified in MURANO.Populations]. VEN+G, the adverse reaction that occurred in 10% of patients was Increased Mortality in Patients with Multiple Myeloma whenneutropenia (26%). The grade 3 adverse reactions that occurred in 2% VENCLEXTA is Added to Bortezomib and Dexamethasone of patients were neutropenia (23%) and anemia (2%). Table 2 presents laboratory abnormalities CLL14.20068717-R1 Venclexta PB-7.5 x 10.5(3.5).indd 1 /08/Nov2021 8:41 AM16-5085 US-VENC-210309 AD.indd 3 11/24/21 2:17 PM'