b'DO NOT RE-SIZEDO NOT RE-SIZEAd unit Project # must match this project # 000-000000US-VENC-200072VENCLEXTA (venetoclax tablets) PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATIONINDICATIONS AND USAGE compared with rates of clinical trials of another drug and may not reflectGrade 4 laboratory abnormalities developing in 2% of patients treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma the rates observed in practice.with VEN+G include neutropenia (32%), leukopenia and lymphopenia VENCLEXTA is indicated for the treatment of adult patients with chronicChronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma(10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%), lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). CLL14 blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia Acute Myeloid Leukemia The safety of VENCLEXTA in combination with obinutuzumab (VEN+G)(2%). VENCLEXTA is indicated in combination with azacitidine, or decitabine, orversus obinutuzumab in combination with chlorambucil (GClb) wasMURANOlow-dose cytarabine for the treatment of newly-diagnosed acute myeloidevaluated in a randomized, open-label, actively controlled trial in patientsThe safety of VENCLEXTA in combination with rituximab (VEN+R) versus leukemia (AML) in adults who are age 75 years or older, or who havewith previously untreated CLL.bendamustine in combination with rituximab (B+R), was evaluated in an comorbidities that preclude use of intensive induction chemotherapy. Patients randomized to the VEN+G arm were treated with VENCLEXTAopen-label randomized study, in patients with CLL who had received at This indication is approved under accelerated approval based on responseand obinutuzumab in combination for six cycles, then with VENCLEXTA asleast one prior therapy. rates. Continued approval for this indication may be contingent uponmonotherapy for an additional six cycles. Patients initiated the first dosePatients randomized to VEN+R completed the scheduled ramp-upverification and description of clinical benefit in confirmatory trials. of the 5-week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and once(5 weeks) and received VENCLEXTA 400 mg once daily in combinationcompleted, continued VENCLEXTA 400 mg once daily for a total of 12with rituximab for 6 cycles followed by single agent VENCLEXTA for a total CONTRAINDICATIONS cycles. The trial required a total Cumulative Illness Rating Scale (CIRS) of 24 months after ramp-up. Patients randomized to B+R received 6 cycles Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation6 or CLcr 70 mL/min, hepatic transaminases and total bilirubin(28 days per cycle) for a total of 6 months. and during the ramp-up phase is contraindicated in patients with 2 times upper limit of normal, and excluded patients with any individualAt the time of analysis, the median duration of exposure was 22 months in CLL/SLL due to the potential for increased risk of tumor lysis syndromeorgan/system impairment score of 4 by CIRS except eye, ear, nose, andthe VEN+R arm compared with 6 months in the B+R arm. [see Drug Interactions].throat organ system.In the VEN+R arm, fatal adverse reactions that occurred in the absence of WARNINGS AND PRECAUTIONS A total of 426 patients were treated (212 with VEN+G, 214 with GClb). Thedisease progression and within 30 days of the last VENCLEXTA treatment Tumor Lysis Syndrome median duration of exposure to VENCLEXTA was 10.5 months (range: 0 toand/or 90 days of last rituximab were reported in 2% (4/194) of patients. Tumor lysis syndrome (TLS), including fatal events and renal failure13.5 months). The median number of cycles was 6 for obinutuzumab andSerious adverse reactions were reported in 46% of patients in the VEN+R requiring dialysis, has occurred in patients with high tumor burden when12 for chlorambucil.arm, with most frequent (5%) being pneumonia (9%). treated with VENCLEXTA [see Adverse Reactions].In the VEN+G arm, fatal adverse reactions that occurred in the absenceIn the VEN+R arm, adverse reactions led to treatment discontinuation in In patients with CLL who followed the current (5 week) dose ramp-upof disease progression and with onset within 28 days of the last study16% of patients, dose reduction in 15%, and dose interruption in 71%. and the TLS prophylaxis and monitoring measures, the rate of TLStreatment were reported in 2% (4/212) of patients, most often fromIn the B+R arm, adverse reactions led to treatment discontinuation in was 2% in the VENCLEXTA CLL monotherapy studies. The rate of TLSinfection. Serious adverse reactions were reported in 49% of patients in10% of patients, dose reduction in 15%, and dose interruption in 40%. remained consistent with VENCLEXTA in combination with obinutuzumabthe VEN+G arm, most often due to febrile neutropenia and pneumoniaIn the VEN+R arm, neutropenia led to dose interruption of VENCLEXTA in or rituximab. With a 2 to 3 week dose ramp-up and higher starting dose(5% each).46% of patients and discontinuation in 3%, and thrombocytopenia led to in patients with CLL/SLL, the TLS rate was 13% and included deaths andIn the VEN+G arm, adverse reactions led to treatment discontinuation indiscontinuation in 3% of patients. renal failure [see Adverse Reactions].16% of patients, dose reduction in 21%, and dose interruption in 74%. InTable 3 presents adverse reactions identified in the MURANO trial. VENCLEXTA can cause rapid reduction in tumor and thus poses a riskthe VEN+G arm, neutropenia led to dose interruption of VENCLEXTA in 41%Table 3. Common (10%) Adverse Reactions in Patients Treated for TLS at initiation and during the ramp-up phase. Changes in bloodof patients, reduction in 13%, and discontinuation in 2%.with VEN+Rchemistries consistent with TLS that require prompt management canTable 1 and Table 2 present adverse reactions and laboratory occur as early as 6 to 8 hours following the first dose of VENCLEXTA andabnormalities identified in the CLL14 trial, respectively. The most commonVENCLEXTA + at each dose increase.(15%) adverse reactions observed with VEN+G were neutropenia,Rituximab The risk of TLS is a continuum based on multiple factors, including tumordiarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.Followed by Single burden and comorbidities. Reduced renal function further increases theTable 1. Common (10%) Adverse Reactions in Patients TreatedAdverse Reaction byAgentBendamustine + risk. Patients should be assessed for risk and should receive appropriatewith VEN+G Body System VENCLEXTARituximab prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor(N = 194) (N = 188)blood chemistries and manage abnormalities promptly. Interrupt dosing ifVENCLEXTA +Obinutuzumab +All GradesGrade 3All GradesGrade 3 needed. Employ more intensive measures (intravenous hydration, frequentObinutuzumabChlorambucil(%) (%) (%) (%)monitoring, hospitalization) as overall risk increases [see Use in SpecificAdverse Reaction by(N = 212) (N = 214)Populations].Body System All GradesGrade 3All GradesGrade 3Blood and lymphatic system disordersConcomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate% % % % Neutropeniaa 65 62 50 44CYP3A inhibitors increases venetoclax exposure, may increase the risk ofaTLS at initiation and during ramp-up phase and requires VENCLEXTA doseBlood and lymphatic system disorders Anemia 16 11 23 14adjustment [see Drug Interactions].Neutropeniaa 60 56 62 52 Gastrointestinal disordersNeutropenia Anemiaa 17 8 20 7 Diarrhea 40 3 17 1In 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 patientsGastrointestinal disorders Nausea 21 1 34 1treated with VENCLEXTA in combination and monotherapy studies (seeDiarrhea 28 4 15 1 Constipation 14 1 21 0Tables 2, 4, 6). Febrile neutropenia occurred in 4% to 6% of patients treated with VENCLEXTA in combination and monotherapy studies [seeNausea 19 0 22 1 Infections and infestationsAdverse Reactions].Constipation 13 0 9 0 Upper respiratory In patients with AML, baseline neutrophil counts worsened in 97% totract infectiona 39 2 23 2100% of patients treated with VENCLEXTA in combination with azacitidineVomiting 10 1 8 1or decitabine or low-dose cytarabine. Neutropenia can recur withLower respiratory18 2 10 2subsequent cycles of therapy.General disorders and administration site conditions tract infectionaMonitor complete blood counts throughout the treatment period. InterruptFatiguea 21 2 23 1 Pneumoniaa 10 7 14 10dosing or reduce dose for severe neutropenia. Consider supportiveInfections and infestations General disorders and administration site conditionsmeasures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Upper respiratory17 1 17 1 Fatiguea 22 2 26 1Infections a tract infectiona aIncludes multiple adverse reaction terms. Fatal and serious infections such as pneumonia and sepsis have occurredIncludes multiple adverse reaction terms. in patients treated with VENCLEXTA [see Adverse Reactions]. MonitorOther clinically important adverse reactions (all grades) reported in 10% patients closely for signs and symptoms of infection and treat promptly.Other clinically important adverse reactions (all Grades) reported in 10%of patients treated with VEN+R are presented below: Withhold VENCLEXTA for Grade 3 and higher infection. of patients treated with VEN+G are presented below:Blood and lymphatic system disorders: febrile neutropenia (4%) Immunization Blood and lymphatic system disorders: febrile neutropenia (6%)Gastrointestinal disorders: vomiting (8%) Do not administer live attenuated vaccines prior to, during, or afterInfection and infestations (all include multiple adverse reaction terms):Infections and infestations: sepsis (1%) treatment with VENCLEXTA until B-cell recovery occurs. The safetypneumonia (9%), urinary tract infection (6%), sepsis (4%)Metabolism and nutrition disorders: tumor lysis syndrome (3%)and efficacy of immunization with live attenuated vaccines during orMetabolism and nutrition disorder: tumor lysis syndrome (1%) following VENCLEXTA therapy have not been studied. Advise patients thatDuring treatment with single agent VENCLEXTA after completion of VEN+GDuring treatment with single agent VENCLEXTA after completion of VEN+R vaccinations may be less effective.combination treatment, the most common all grade adverse reactioncombination treatment, the most common all grade adverse reactions Embryo-Fetal Toxicity (10% patients) reported was neutropenia (26%). The most common(10% patients) reported were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections Based on its mechanism of action and findings in animals, VENCLEXTAgrade 3 adverse reactions (2% patients) were neutropenia (23%), and(11%). The most common Grade 3 or 4 adverse reactions (2% patients) may cause embryo-fetal harm when administered to a pregnant woman.anemia (2%).were neutropenia (12%) and anemia (3%). In an embryo-fetal study conducted in mice, administration of venetoclaxTable 2. New or Worsening Clinically Important LaboratoryTable 4 describes common treatment-emergent laboratory abnormalities to pregnant animals at exposures equivalent to that observed in patients atAbnormalities Occurring at 10% in Patients Treated with VEN+G identified in the MURANO trial. a dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. There are no adequate and well-controlled studies inVENCLEXTA +Obinutuzumab +Table 4. New or Worsening Clinically Important Laboratory pregnant women using VENCLEXTA. Advise females of reproductiveObinutuzumabChlorambucilAbnormalities Occurring at 10% (All Grades) in Patients Treated potential to avoid pregnancy during treatment. If VENCLEXTA is used(N = 212) (N = 214) with VEN+Rduring pregnancy or if the patient becomes pregnant while takingLaboratorya AllGrade 3AllGrade 3 VENCLEXTA, the patient should be apprised of the potential hazard to theAbnormality Gradesor 4Gradesor 4VENCLEXTA +Bendamustine + fetus [see Use in Specific Populations].(%) (%) (%) (%) RituximabRituximab Increased Mortality in Patients with Multiple Myeloma whenHematology Laboratory(N = 194) (N = 188)VENCLEXTA is Added to Bortezomib and Dexamethasone Abnormality Alla Grade 3Alla Grade 3 In a randomized trial (BELLINI; NCT02755597) in patients with relapsed Leukopenia 90 46 89 41 Gradesor 4Gradesor 4 or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib Lymphopenia 87 57 87 51 (%) (%) (%) (%)plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted Neutropenia 83 63 79 56 Hematologyin increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not Thrombocytopenia 68 28 71 26Leukopenia 89 46 81 35recommended outside of controlled clinical trials.Anemia 53 15 46 11Lymphopenia 87 56 79 55ADVERSE REACTIONS ChemistryNeutropenia 86 64 84 59The following clinically significant adverse reactions are discussed inBlood creatinine Anemia 50 12 63 15greater detail in other sections of the labeling:increased 80 6 74 2 Tumor Lysis Syndrome [see Warnings and Precautions]Thrombocytopenia 49 15 60 20 Neutropenia [see Warnings and Precautions]Hypocalcemia 67 9 58 4 Infections [see Warnings and Precautions]Hyperkalemia 41 4 35 3 ChemistryClinical Trials Experience Hyperuricemia 38 38 38 38 Blood creatinine77 1 78 1Because clinical trials are conducted under widely variable conditions,aIncludes laboratory abnormalities that were new or worsening, or withincreasedadverse event rates observed in clinical trials of a drug cannot be directlyworsening from baseline unknown. Hypocalcemia 62 5 51 220064248-R1 Venclexta PB-7.5 x 10.5(3).indd 1 07 Jul 2020 12:41 PM'