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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 FDA approved 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 previously treated CLL patients 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 woman 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

Adverse Reaction

Any Grade (%)

N = 240

Grade 3 or 4 (%)

N = 240

Table 1 . continued

Body System

Gastrointestinal disorders

General disorders and administration site conditions

Infections and infestations

Adverse Reaction

Any Grade (%)

N = 240

Metabolic and nutrition disorders

Hypokalemia 12 4

Musculoskeletal and connective tissue Back pain 10 < 1 disorders

Nervous system disorders

Headache 15 < 1

Respiratory , thoracic , and mediastinal Cough 13 0 disorders

Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0 . a Neutropenia / neutrophil count decreased . b Anemia / hemoglobin decreased . c Thrombocytopenia / platelet count decreased .

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 12 % ( 9 / 77 ; 4 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 μmol / 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

Parameter

All Grades (%) N = 66

Laboratory TLS a 6 6 Hyperkalemia b 20 2 Hyperphosphatemia c 15 3 Hypocalcemia d 9 3 Hyperuricemia e 6 2 a Laboratory abnormalities that met ≥2 of the following criteria within

24 hours of each other : potassium > 6 mmol / L , uric acid > 476 μmol / L , calcium < 1.75 mmol / L , or phosphorus > 1.5 mmol / L ; or were reported as TLS events . b Hyperkalemia / blood potassium increased . c Hyperphosphatemia / blood phosphorus increased . d Hypocalcemia / blood calcium decreased . e Hyperuricemia / blood uric acid increased .

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 .

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 , azithromycin , 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 .

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

Avoid grapefruit products , Seville oranges , and starfruit during treatment with VENCLEXTA , as they contain inhibitors of CYP3A .

Grade 3 or 4 Co-administration of a single dose of rifampin , a P-gp inhibitor , increased

(%) venetoclax Cmax by 106 % and AUC

N = 240 ∞ 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 Cmax 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 In vitro data suggest venetoclax has inhibition potential on P-gp substrates at therapeutic dose levels in the gut . 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

Grade ≥3 (%) Females of reproductive potential should undergo pregnancy testing before

N = 66 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 17 % 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 on results of the population pharmacokinetic analysis , a trend for increased adverse events was observed in patients with moderate hepatic impairment ; monitor these patients more closely for signs of toxicity during the initiation and dose ramp-up phase . A recommended dose has not been determined for patients with severe hepatic impairment .