b'DO NOT RE-SIZEDO NOT RE-SIZEAd unit Project # must match this project # 000-000000US-VENC-220137VENCLEXTA (venetoclax tablets) PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATIONINDICATIONS AND USAGE in increased mortality. Treatment of patients with multiple myeloma withTable 2. New or Worsening Clinically Important Laboratory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA in combination with bortezomib plus dexamethasone is notAbnormalities (10%) in Patients Treated with VEN+G in CLL14VENCLEXTA is indicated for the treatment of adult patients with chronicrecommended outside of controlled clinical trials.lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ADVERSE REACTIONS VENCLEXTA +Obinutuzumab Obinutuzumab + Chlorambucil Acute Myeloid Leukemia The following clinically significant adverse reactions are describeda (N = 212) (N = 214)VENCLEXTA is indicated in combination with azacitidine, or decitabine, orelsewhere in the labeling:Laboratory Abnormality AllGradeAllGrade low-dose cytarabine for the treatment of newly diagnosed acute myeloid Tumor Lysis Syndrome [see Warnings and Precautions] Grades 3 or 4 Grades 3 or 4leukemia (AML) in adults 75 years or older, or who have comorbidities that Neutropenia [see Warnings and Precautions] (%) (%) (%) (%)preclude use of intensive induction chemotherapy.Infections [see Warnings and Precautions] HematologyCONTRAINDICATIONS Clinical Trials Experience Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiationBecause clinical trials are conducted under widely variable conditions, Leukopenia 90 46 89 41and during the ramp-up phase is contraindicated in patients with adverse event rates observed in clinical trials of a drug cannot be directly Lymphopenia 87 57 87 51CLL/SLL due to the potential for increased risk of tumor lysis syndromecompared with rates of clinical trials of another drug and may not reflect Neutropenia 83 63 79 56[see Drug Interactions].the rates observed in practice. Thrombocytopenia 68 28 71 26WARNINGS AND PRECAUTIONS In CLL/SLL, the safety population reflects exposure to VENCLEXTA as Tumor Lysis Syndrome monotherapy in patients in M13-982, M14-032, and M12-175 and in Anemia 53 15 46 11Tumor lysis syndrome (TLS), including fatal events and renal failurecombination with obinutuzumab or rituximab in patients in CLL14 andChemistryrequiring dialysis, has occurred in patients treated with VENCLEXTA [seeMURANO. In this CLL/SLL safety population, the most common adverse Blood creatinine increased 80 6 74 2Adverse Reactions].reactions (20%) for VENCLEXTA were neutropenia, thrombocytopenia, VENCLEXTA can cause rapid reduction in tumor and thus poses a risk foranemia, diarrhea, nausea, upper respiratory tract infection, cough, Hypocalcemia 67 9 58 4TLS at initiation and during the ramp-up phase in all patients, and duringmusculoskeletal pain, fatigue, and edema. Hyperkalemia 41 4 35 3reinitiation after dosage interruption in patients with CLL/SLL. Changes inIn AML, the safety population reflects exposure to VENCLEXTA in Hyperuricemia 38 38 38 38blood chemistries consistent with TLS that require prompt managementcombination with decitabine, azacitidine, or low-dose cytarabine inaIncludes laboratory abnormalities that were new or worsening, or with can occur as early as 6 to 8 hours following the first dose of VENCLEXTApatients in M14-358, VIALE-A, and VIALE-C. In this safety population,worsening from baseline unknown.and at each dose increase. TLS, including fatal cases, has been reportedthe most common adverse reactions (30% in any trial) were nausea, after a single 20 mg dose of VENCLEXTA. diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia,Grade 4 laboratory abnormalities that developed in 2% of patients treated In patients with CLL/SLL who followed the current (5-week) dose ramp-upfatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage,with VEN+G included neutropenia (32%), leukopenia and lymphopenia and the TLS prophylaxis and monitoring measures, the rate of TLS wasanemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness,(10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), 2% in the VENCLEXTA CLL/SLL monotherapy trials. The rate of TLScough, oropharyngeal pain, and hypotension. blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia remained consistent with VENCLEXTA in combination with obinutuzumabChronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma(2%). or rituximab. With a 2- to 3-week dose ramp-up and higher starting doseVENCLEXTA in Combination with ObinutuzumabVENCLEXTA in Combination with Rituximab in patients with CLL/SLL, the TLS rate was 13% and included deaths andThe safety of VENCLEXTA in combination with obinutuzumab (VEN+G)The safety of VENCLEXTA in combination with rituximab (VEN+R) (N=194) renal failure [see Adverse Reactions].(N=212) versus obinutuzumab in combination with chlorambucil (GClb)versus bendamustine in combination with rituximab (B+R) (N=188) was In patients with AML who followed the current 3-day ramp-up dosing(N=214) was evaluated in CLL14, a randomized, open-label, activelyevaluated in MURANO. Patients randomized to VEN+R completed the schedule and the TLS prophylaxis and monitoring measures, the rate ofcontrolled trial in patients with previously untreated CLL. Patientsscheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once TLS was 1.1% in patients who received VENCLEXTA in combination withrandomized to the VEN+G arm were treated with VENCLEXTA anddaily, in combination with rituximab for 6 cycles followed by VENCLEXTA azacitidine (VIALE-A). In patients with AML who followed a 4-day ramp-upobinutuzumab in combination for six cycles, then with VENCLEXTA asmonotherapy, for a total of 24 months after ramp-up. At the time of dosing schedule and the TLS prophylaxis and monitoring measures, themonotherapy for an additional six cycles. Patients initiated the first doseanalysis, the median duration of exposure to VENCLEXTA was 22 months rate of TLS was 5.6% and included deaths and renal failure in patientsof the 5-week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and onceand the median number of cycles of rituximab was 6 in the VEN+R arm. who received VENCLEXTA in combination with low-dose cytarabinecompleted, continued VENCLEXTA 400 mg orally once daily for a totalSerious adverse reactions were reported in 46% of patients in the VEN+R (VIALE-C) [see Adverse Reactions]. of 12 cycles. The trial required a total Cumulative Illness Rating Scalearm, with most frequent (5%) being pneumonia (9%). Fatal adverse The risk of TLS is a continuum based on multiple factors, particularly(CIRS) 6 or CLcr 70 mL/min, hepatic transaminases and total bilirubinreactions that occurred in the absence of disease progression and within reduced renal function, tumor burden, and type of malignancy.2 times upper limit of normal and excluded patients with any individual30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab Splenomegaly may also increase the risk of TLS in patients with CLL/SLL. organ/system impairment score of 4 by CIRS except eye, ear, nose, andwere reported in 2% (4/194) of patients. Assess all patients for risk and provide appropriate prophylaxis for TLS,throat organ system. The median duration of exposure to VENCLEXTA wasIn the VEN+R arm, adverse reactions led to treatment discontinuation including hydration and anti-hyperuricemics. Monitor blood chemistries10.5 months (range: 0 to 13.5 months) and the median number of cyclesin 16% of patients, dose reduction in 15%, and dose interruption in and manage abnormalities promptly. Employ more intensive measuresof obinutuzumab was 6 in the VEN+G arm. 71%. Neutropenia and thrombocytopenia each led to discontinuation of (intravenous hydration, frequent monitoring, hospitalization) as overall riskSerious adverse reactions were reported in 49% of patients in theVENCLEXTA in 3% of patients. Neutropenia led to dose interruption of increases. Interrupt dosing if needed; when restarting VENCLEXTA, followVEN+G arm, most often due to febrile neutropenia and pneumonia (5%VENCLEXTA in 46% of patients.dose modification guidance [see Dosage and Administration in the fulleach). Fatal adverse reactions that occurred in the absence of diseaseTable 3 presents adverse reactions identified in MURANO.Prescribing Information and see Use in Specific Populations].progression and with onset within 28 days of the last study treatment wereTable 3. Adverse Reactions (10%) in Patients Treated with VEN+R Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderatereported in 2% (4/212) of patients, most often from infection.in MURANOCYP3A inhibitors increases venetoclax exposure, which may increase theIn the VEN+G arm, adverse reactions led to treatment discontinuation in risk of TLS at initiation and during the ramp-up phase of VENCLEXTA.16% of patients, dose reduction in 21%, and dose interruption in 74%.VENCLEXTA +Bendamustine + For patients with CLL/SLL, coadministration of VENCLEXTA with strongNeutropenia led to discontinuation of VENCLEXTA in 2% of patients, doseRituximab RituximabCYP3A inhibitors at initiation and during the 5-week ramp-up phase isreduction in 13%, and dose interruption in 41%. Adverse Reaction(N = 194) (N = 188)contraindicated [see Contraindications]. For patients with AML, reduce theTable 1 presents adverse reactions identified in CLL14.All Grades Grade 3 All Grades Grade 3dose of VENCLEXTA when coadministered with strong CYP3A inhibitors atTable 1. Adverse Reactions (10%) in Patients Treated with VEN+G(%) (%) (%) (%)initiation and during the 3- or 4-day ramp-up phase. For patients with in CLL14CLL/SLL or AML, reduce the dose of VENCLEXTA when coadministeredBlood and lymphatic system disorderswith moderate CYP3A4 inhibitors or P-gp inhibitors [see Drug Interactions].VENCLEXTA +Obinutuzumab +Neutropeniaa 65 62 50 44Neutropenia Obinutuzumab Chlorambucil aIn patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64%Adverse Reaction(N = 212) (N = 214) Anemia 16 11 23 14of patients and Grade 4 neutropenia developed in 31% to 33% of patientsAll Grades Grade 3 All Grades Grade 3 Gastrointestinal disorderswhen treated with VENCLEXTA in combination and monotherapy studies.(%) (%) (%) (%) Diarrhea 40 3 17 1Febrile neutropenia occurred in 4% to 6% of patients [see AdverseBlood and lymphatic system disorders Nausea 21 1 34 1Reactions]. In patients with AML, baseline neutrophil counts worsened in 95% to Neutropeniaa 60 56 62 52 Constipation 14 1 21 0100% of patients treated with VENCLEXTA in combination with azacitidine, Anemiaa 17 8 20 7 Infections and infestationsdecitabine, or low-dose cytarabine. Neutropenia can recur with subsequentGastrointestinal disorders Upper respiratorycycles.tract infectiona 39 2 23 2Monitor complete blood counts throughout the treatment period. Consider Diarrhea 28 4 15 1supportive measures, including antimicrobials and growth factors (e.g., Nausea 19 0 22 1 Lower respiratory 18 2 10 2G-CSF).tract infectionaInfectionsConstipation 13 0 9 0 Pneumoniaa 10 7 14 10Fatal and serious infections, such as pneumonia and sepsis, have occurred Vomiting 10 1 8 1 General disorders and administration site conditionsin patients treated with VENCLEXTA [see Adverse Reactions].General disorders and administration site conditions Fatiguea 22 2 26 1Monitor patients for signs and symptoms of infection and treat promptly. Fatiguea 21 2 23 1 aIncludes multiple adverse reaction terms. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution.Infections and infestationsImmunization Other clinically important adverse reactions (All Grades) reported in 10%Upper respiratory of patients treated with VEN+R are presented below: Do not administer live attenuated vaccines prior to, during, or aftera 17 1 17 1treatment with VENCLEXTA until B-cell recovery occurs. The safety tract infection Blood and lymphatic system disorders: febrile neutropenia (4%) and efficacy of immunization with live attenuated vaccines during oraIncludes multiple adverse reaction terms.Gastrointestinal disorders: vomiting (8%) following VENCLEXTA therapy have not been studied. Advise patients thatOther clinically important adverse reactions (All Grades) reported in 10%Infections and infestations: sepsis (1%) vaccinations may be less effective.of patients treated with VEN+G are presented below:Metabolism and nutrition disorders: tumor lysis syndrome (3%)Embryo-Fetal Toxicity Blood and lymphatic system disorders: febrile neutropenia (6%)During treatment with VENCLEXTA monotherapy after completion of Based on findings in animals and its mechanism of action, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman.Infection and infestations (all include multiple adverse reaction terms):VEN+R combination treatment, adverse reactions that occurred in 10% In an embryo-fetal study conducted in mice, administration of venetoclaxpneumonia (9%), urinary tract infection (6%), sepsis (4%)of patients were upper respiratory tract infection (21%), diarrhea (19%), to pregnant animals at exposures equivalent to that observed in patients atMetabolism and nutrition disorder: tumor lysis syndrome (1%)neutropenia (16%), and lower respiratory tract infections (11%). The Grade 3 or 4 adverse reactions that occurred in 2% of patients were a dose of 400 mg daily resulted in post-implantation loss and decreasedDuring treatment with VENCLEXTA monotherapy after completion ofneutropenia (12%) and anemia (3%). fetal weight.VEN+G, the adverse reaction that occurred in 10% of patients wasTable 4 presents laboratory abnormalities identified in MURANO.Advise pregnant women of the potential risk to a fetus. Advise femalesneutropenia (26%). The grade 3 adverse reactions that occurred in 2% of reproductive potential to use effective contraception during treatmentof patients were neutropenia (23%) and anemia (2%). with VENCLEXTA and for 30 days after the last dose [see Use in SpecificTable 2 presents laboratory abnormalities CLL14.Populations].Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and DexamethasoneIn 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 20070720 Venclexta PB-7.5 x 10.5(3.5).indd 1 /29/Jun2022 2:29 PM'