ASH Clinical News ACN_4.4_SUPP_Digital Version | Page 10

VENCLEXTA TM ( venetoclax ) tablets

INDICATIONS AND USAGE VENCLEXTA is indicated for the treatment of patients with chronic lymphocytic leukemia ( CLL ) with 17p deletion , as detected by an FDAapproved test , who have received at least one prior therapy . This indication is approved under accelerated approval based on overall response rate . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial . CONTRAINDICATIONS Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated [ see Drug Interactions ]. WARNINGS AND PRECAUTIONS Tumor Lysis Syndrome Tumor lysis syndrome , including fatal events and renal failure requiring dialysis , has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLEXTA [ see Adverse Reactions ]. VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase . Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase . The risk of TLS is a continuum based on multiple factors , including tumor burden and comorbidities . Reduced renal function ( CrCl < 80 mL / min ) further increases the risk . Patients should be assessed for risk and should receive appropriate prophylaxis for TLS , including hydration and anti-hyperuricemics . Monitor blood chemistries and manage abnormalities promptly . Interrupt dosing if needed . Employ more intensive measures ( intravenous hydration , frequent monitoring , hospitalization ) as overall risk increases [ see Use in Specific Populations ]. Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors and P-gp inhibitors increases venetoclax exposure , may increase the risk of TLS at initiation and during ramp-up phase , and may require VENCLEXTA dose adjustment [ see Drug Interactions ]. Neutropenia Grade 3 or 4 neutropenia occurred in 41 % ( 98 / 240 ) of patients treated with VENCLEXTA [ see Adverse Reactions ]. 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 ). 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 embryo-fetal harm when administered to a pregnant woman . In an embryo-fetal study conducted in mice , administration of venetoclax to pregnant animals at exposures equivalent to that observed in patients at the recommended dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight . There are no adequate and well-controlled studies in pregnant women using VENCLEXTA . Advise females of reproductive potential to avoid pregnancy during treatment . If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while taking VENCLEXTA , the patient should be apprised of the potential hazard to the fetus [ see Use in Specific Populations ]. ADVERSE REACTIONS The following serious adverse events are discussed in greater detail in other sections of the labeling :

• Tumor Lysis Syndrome [ see Warnings and Precautions ]

• Neutropenia [ see Warnings and Precautions ]

Because clinical trials are conducted under widely variable conditions , adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice . Clinical Trial Experience The safety of single agent VENCLEXTA at the 400 mg recommended daily dose following a dose ramp-up schedule is based on pooled data of 240 patients with previously treated CLL from two phase 2 trials and one phase 1 trial . In the pooled dataset , the median age was 66 years ( range : 29 to 85 years ), 95 % were white , and 69 % were male . The median number of prior therapies was 3 ( range : 1 to 12 ). The median duration of treatment with VENCLEXTA at the time of data analysis was approximately 10.3 months ( range : 0 to 34.1 months ). Approximately 46 % of patients received VENCLEXTA for more than 48 weeks . The most common adverse reactions ( ≥20 %) of any grade were neutropenia , diarrhea , nausea , anemia , upper respiratory tract infection , thrombocytopenia , and fatigue . Serious adverse reactions were reported in 43.8 % of patients . The most frequent serious adverse reactions ( ≥2 %) were pneumonia , febrile neutropenia , pyrexia , autoimmune hemolytic anemia ( AIHA ), anemia , and TLS . Discontinuations due to adverse reactions occurred in 8.3 % of patients . The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and AIHA . Dosage adjustments due to adverse reactions occurred in 9.6 % of patients . The most frequent adverse reactions leading to dose adjustments were neutropenia , febrile neutropenia , and thrombocytopenia . Adverse reactions reported in 3 trials of patients with previously treated CLL using single agent VENCLEXTA are presented in Table 1 .

Table 1 . Adverse Reactions Reported in ≥10 % ( Any Grade ) or ≥5 % ( Grade 3 or 4 ) of Patients with CLL

Body System

Blood and lymphatic system disorders

Body System

Gastrointestinal disorders

General disorders and administration site conditions

Infections and infestations

Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA . In the initial Phase 1 dose-finding trials , which had shorter ( 2-3 week ) ramp-up phase and higher starting dose , the incidence of TLS was 13 % ( 10 / 77 ; 5 laboratory TLS , 5 clinical TLS ), including 2 fatal events and 3 events of acute renal failure , 1 requiring dialysis . The risk of TLS was reduced after revision of the dosing regimen and modification to prophylaxis and monitoring measures . In venetoclax clinical trials , patients with any measurable lymph node ≥10 cm or those with both an ALC ≥25 x 10 9 / L and any measurable lymph node ≥5 cm were hospitalized to enable more intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the ramp-up phase . In 66 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg , the rate of TLS was 6 %. All events either met laboratory TLS criteria ( laboratory abnormalities that met ≥2 of the following within 24 hours of each other : potassium > 6 mmol / L , uric acid > 476 µ mol / L , calcium < 1.75 mmol / L , or phosphorus > 1.5 mmol / L ); or were reported as TLS events . The events occurred in patients who had a lymph node ( s ) ≥5 cm or ALC ≥25 x 10 9 / L . No TLS with clinical consequences such as acute renal failure , cardiac arrhythmias or sudden death and / or seizures was observed in these patients . All patients had CrCl ≥50 mL / min . Laboratory abnormalities relevant to TLS observed in 66 patients with CLL who followed the dose ramp-up schedule and TLS prophylaxis measures are presented in Table 2 .

Table 2 . Adverse Reactions of TLS and Relevant Laboratory Abnormalities Reported in Patients with CLL

DRUG INTERACTIONS Effects of Other Drugs on VENCLEXTA Venetoclax is predominantly metabolized by CYP3A4 / 5 . Strong CYP3A Inhibitors Concomitant use of VENCLEXTA with strong CYP3A inhibitors ( e . g ., ketoconazole , conivaptan , clarithromycin , indinavir , itraconazole , lopinavir , ritonavir , telaprevir , posaconazole and voriconazole ) at initiation and during ramp-up phase is contraindicated [ see Contraindications ]. For patients who have completed the ramp-up phase and are on a steady daily dose of VENCLEXTA , reduce the VENCLEXTA dose by at least 75 % when used concomitantly with strong CYP3A inhibitors . Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor .

Co-administration of ketoconazole increased venetoclax C max by 2.3-fold and AUC ∞ by 6.4-fold .

Co-administration of ritonavir increased venetoclax C max by 2.4-fold and AUC by 7.9-fold . 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

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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 %. CYP3A Inducers Avoid concomitant use of VENCLEXTA with strong CYP3A inducers ( e . g ., carbamazepine , phenytoin , rifampin , St . John ’ s wort ) or moderate CYP3A inducers ( e . g ., bosentan , efavirenz , etravirine , modafinil , nafcillin ). Consider alternative treatments with less CYP3A induction . Co-administration of multiple doses of rifampin , a strong CYP3A inducer , decreased venetoclax Cmax by 42 % and AUC ∞ by 71 %. Effects of VENCLEXTA on Other Drugs Warfarin In a drug-drug interaction study in healthy subjects , administration of a single dose of venetoclax with warfarin resulted in an 18 % to 28 % increase in C max and AUC ∞ of R-warfarin and S-warfarin . Because venetoclax was not dosed to steady state , it is recommended that the international normalized ratio ( INR ) be monitored closely in patients receiving warfarin . P-gp substrates Administration of a single 100 mg dose of venetoclax with digoxin resulted in a 35 % increase in digoxin Cmax and a 9 % increase in AUC ∞ . Therefore , co-administration of narrow therapeutic index P-gp substrates ( e . g ., digoxin , everolimus , and sirolimus ) with VENCLEXTA should be avoided . If a narrow therapeutic index P-gp substrate must be used , it should be taken at least 6 hours before VENCLEXTA . USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no available human data on the use of VENCLEXTA in pregnant women . Based on toxicity observed in mice , VENCLEXTA may cause fetal harm when administered to pregnant women . In mice , venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at the recommended human dose of 400 mg daily . 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 . The background risk in the U . S . general population of major birth defects is 2 % to 4 % and of miscarriage is 15 % to 20 % of clinically recognized pregnancies . Data Animal data In embryo-fetal development studies , venetoclax was administered to pregnant mice and rabbits during the period of organogenesis . In mice , venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg / kg / day ( maternal exposures approximately 1.2 times the human AUC exposure at the recommended dose of 400 mg daily ). No teratogenicity was observed in either the mouse or the rabbit . Lactation Risk Summary 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 . Because many drugs are excreted in human milk and because the potential for serious adverse reactions in breastfed infants from VENCLEXTA is unknown , advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA . Females and Males of Reproductive Potential VENCLEXTA may cause fetal harm [ see Warnings and Precautions and Use in Specific Populations ]. Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of VENCLEXTA [ see Use in Specific Populations ]. Contraception Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose [ see Use in Specific Populations ]. Infertility Based on findings in animals , male fertility may be compromised by treatment with VENCLEXTA [ see Nonclinical Toxicology ]. Pediatric Use Safety and effectiveness have not been established in pediatric patients . Geriatric Use Of the 106 patients with previously treated CLL with 17p deletion who were evaluated for efficacy , 57 % were ≥65 years of age and 18 % were ≥75 years of age . Of the 240 patients with previously treated CLL evaluated for safety from 3 open-label trials , 58 % were ≥65 years of age and 17 % were ≥75 years of age . No overall differences in safety and effectiveness were observed between older and younger patients . Renal Impairment Patients with reduced renal function ( CrCl < 80 mL / min ) are at increased risk of TLS . These patients may require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with VENCLEXTA . No specific clinical trials have been conducted in subjects with renal impairment . Less than 0.1 % of radioactive VENCLEXTA dose was detected in urine . No dose adjustment is needed for patients with mild or moderate renal impairment ( CrCl ≥30 mL / min ) based on results of the population pharmacokinetic analysis . A recommended dose has not been determined for patients with severe renal impairment ( CrCl < 30 mL / min ) or patients on dialysis . Hepatic Impairment No specific clinical trials have been conducted in subjects with hepatic impairment , however human mass balance study showed that venetoclax undergoes hepatic elimination . Although no dose adjustment is recommended in patients with mild or moderate hepatic impairment based