VENCLEXTA ® ( venetoclax tablets ) PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE VENCLEXTA is indicated for the treatment of patients with chronic lymphocytic leukemia ( CLL ) or small lymphocytic lymphoma ( SLL ), with or without 17p deletion , who have received at least one prior therapy . CONTRAINDICATIONS Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated due to the potential for increased risk of tumor lysis syndrome [ see Dosage and Administration ( 2.4 ) in the Full Prescribing Information and Drug Interactions ]. WARNINGS AND PRECAUTIONS Tumor Lysis Syndrome Tumor lysis syndrome ( TLS ), 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 ]. With the current ( 5 week ) dose ramp-up , TLS prophylaxis and monitoring , the rate of TLS was 2 % in the VENCLEXTA monotherapy studies . The rate of TLS remained consistent with VENCLEXTA in combination with rituximab . With a 2-3 week dose ramp-up and higher starting dose in patients with CLL , the TLS rate was 13 % and included deaths and renal failure . 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 Dosage and Administration ( 2.2 , 2.3 ) in the Full Prescribing Information and 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 Dosage and Administration ( 2.4 ) in the Full Prescribing Information and Drug Interactions ]. Neutropenia Grade 3 or 4 neutropenia developed in 64 % ( 124 / 194 ) of patients and Grade 4 neutropenia developed in 31 % of patients treated with VENCLEXTA in combination with rituximab ( see Table 2 ). Grade 3 or 4 neutropenia developed in 63 % ( 216 / 344 ) of patients and Grade 4 neutropenia developed in 33 % of patients treated with VENCLEXTA monotherapy ( see Table 4 ). Febrile neutropenia occurred in 4 % of patients treated with VENCLEXTA in combination with rituximab and in 6 % of patients treated with VENCLEXTA monotherapy [ 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 ) [ see Dosage and Administration ( 2.3 ) in the Full Prescribing Information ]. 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 ] Clinical Trial Experience 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 . MURANO The safety of VENCLEXTA in combination with rituximab ( VEN + R ) versus bendamustine in combination with rituximab ( B + R ), was evaluated in an openlabel randomized study , in patients with CLL who had received at least one prior therapy . Patients randomized to VEN + R completed the scheduled ramp-up ( 5 weeks ) and received VENCLEXTA 400 mg once daily in combination with rituximab for 6 cycles followed by single agent VENCLEXTA for a total of 24 months after rampup . Patients randomized to B + R received 6 cycles ( 28 days per cycle ) for a total of 6 months . A total of 389 patients were randomized : 194 to the VEN + R arm and 195 to the B + R arm . The median age was 65 years ( range : 22-85 years ), 97 % were white , 74 % were male , and 99 % had ECOG performance status < 2 . Median prior lines of therapy was 1 ( range : 1-5 ); 59 % had received 1 prior therapy , 26 % had received 2 prior therapies , and 16 % had received 3 or more prior therapies . At the time of analysis , the median duration of exposure was 22 months in the VEN + R arm compared with 6 months in the B + R arm . In the VEN + R arm , fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and / or 90 days of last rituximab were reported in 2 % ( 4 / 194 ) of patients . Serious adverse reactions were reported in 46 % of patients in the VEN + R arm , with most frequent ( ≥5 %) being pneumonia ( 9 %). In the VEN + R arm , adverse reactions led to treatment discontinuation in 16 % of patients , dose reduction in 15 %, and dose interruption in 71 %. In the B + R arm , adverse reactions led to treatment discontinuation in 10 % of patients , dose reduction in 15 %, and dose interruption in 40 %. In the VEN + R arm , neutropenia led to dose interruption of VENCLEXTA in 46 % of patients and discontinuation in 3 %, and thrombocytopenia led to discontinuation in 3 % of patients . Table 1 and Table 2 present adverse reactions and laboratory abnormalities , respectively , identified in the MURANO trial . The MURANO trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for VEN + R as compared with B + R , for any specific adverse reaction or laboratory abnormality . Table 1 . Common ( ≥10 %) Adverse Reactions Reported with ≥5 % Higher All-Grade or ≥2 % Higher Grade ≥3 Incidence in Patients Treated with VEN + R Compared with B + R Adverse Reaction by Body System VENCLEXTA + Rituximab Followed by Single Agent VENCLEXTA ( N = 194 ) Bendamustine + Rituximab ( N = 188 ) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Blood & lymphatic system disorders Neutropenia a 65 62 50 44 Gastrointestinal disorders Diarrhea 40 3 17 1 Infections & infestations Upper respiratory tract infection a 39 2 23 2 Lower respiratory tract infection a 18 2 10 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 19 1 13 0 Metabolism and nutrition disorders Tumor lysis syndrome 3 3 1 1 a Includes multiple adverse reaction terms . Other adverse reactions ( all Grades ) reported in ≥10 % of patients in the VEN + R arm in MURANO , and other important adverse reactions are presented below : Blood & lymphatic system disorders : anemia ( 16 %), thrombocytopenia ( 15 %), febrile neutropenia ( 4 %) Gastrointestinal disorders : nausea ( 21 %), constipation ( 14 %), abdominal pain ( 13 %), mucositis ( 10 %), vomiting ( 8 %) Respiratory disorders : cough ( 22 %) General disorders and administration site conditions : fatigue ( 22 %), pyrexia ( 15 %) Skin disorders : rash ( 13 %) Nervous system and psychiatric disorders : headache ( 11 %), insomnia ( 11 %) Infections & infestations : pneumonia ( 10 %) During treatment with single agent VENCLEXTA after completion of VEN + R combination treatment , the most common all grade adverse reactions ( ≥10 % patients ) reported were upper respiratory tract infection ( 21 %), diarrhea ( 19 %), neutropenia ( 16 %), and lower respiratory tract infections ( 11 %). The most common grade 3 or 4 adverse reaction ( ≥2 % patients ) were neutropenia ( 12 %) and anemia ( 3 %). Laboratory Abnormalities Table 2 describes common treatment-emergent laboratory abnormalities identified in the MURANO trial . Table 2 . Common ( ≥10 %) New or Worsening Laboratory Abnormalities Occurring at ≥5 % ( Any Grade ) or ≥2 % ( Grade 3 or 4 ) Higher Incidence with VEN + R compared with B + R VENCLEXTA + Rituximab N = 194 Bendamustine + Rituximab N = 188 Laboratory Abnormality All Grades a (%) Grade 3 or 4 (%) All Grades a (%) Grade 3 or 4 (%) Hematology Leukopenia 89 46 81 35 Lymphopenia 87 56 79 55 Neutropenia 86 64 84 59 Chemistry Hypocalcemia 62 5 51 2 Hypophosphatemia 57 14 35 4 AST / SGOT increased 46 2 31 3 Hyperuricemia 36 36 33 33 Alkaline phosphatase increased 35 1 20 1 Hyperbilirubinemia 33 4 26 3 Hyponatremia 30 6 20 3 Hypokalemia 29 6 18 3 Hyperkalemia 24 3 19 2 Hypernatremia 24 1 13 0 Hypoglycemia 16 2 7 0 a Includes laboratory abnormalities that were new or worsening , or with worsening from baseline unknown . New Grade 4 laboratory abnormalities reported in ≥2 % of patients treated with VEN + R included neutropenia ( 31 %), lymphopenia ( 16 %), leukopenia ( 6 %), thrombocytopenia ( 6 %), hyperuricemia ( 4 %), hypocalcemia ( 2 %), hypoglycemia ( 2 %), and hypermagnesemia ( 2 %). Monotherapy Studies ( M13-982 , M14-032 , and M12-175 ) The safety of single agent VENCLEXTA at the 400 mg recommended daily dose following a dose ramp-up schedule is based on pooled data from three single-arm trials ( M13-982 , M14-032 , and M12-175 ). In the pooled dataset , consisting of 352 patients with previously treated CLL or SLL , the median age was 66 years ( range : 28 to 85 years ), 93 % were white , and 68 % were male . The median number of prior therapies was 3 ( range : 0 to 15 ). The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months ( range : 0 to 50 months ). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks . Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2 % of patients in the VENCLEXTA monotherapy studies , most commonly ( 2 patients ) from septic shock . Serious adverse reactions were reported in 52 % of patients , with the most frequent ( ≥5 %) being pneumonia ( 9 %), febrile neutropenia ( 5 %), and sepsis ( 5 %). Adverse reactions led to treatment discontinuation in 9 % of patients , dose reduction in 13 %, and dose interruption in 36 %. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia . The most frequent adverse reaction ( ≥5 %) leading to dose reductions or interruptions was neutropenia ( 8 %). Adverse reactions identified in these trials of single-agent VENCLEXTA are presented in Table 3 . Table 3 . Adverse Reactions Reported in ≥10 % ( Any Grade ) or ≥5 % ( Grade ≥3 ) of Patients with Previously Treated CLL ( VENCLEXTA Monotherapy ) Body System Adverse Reaction Any Grade (%) N = 352 Grade ≥3 (%) N = 352 Blood and lymphatic system disorders Neutropenia a 50 45 Anemia a 33 18 Thrombocytopenia a 29 20 Lymphopenia a 11 7 Febrile neutropenia 6 6 Gastrointestinal disorders Diarrhea 43 3 Nausea 42 1 Abdominal pain a 18 3 Vomiting 16 1 Constipation 16 < 1 Mucositis a 13 < 1 General disorders and administration site conditions Fatigue a 32 4 Edema a 22 2 Pyrexia 18 < 1 Infections and infestations Upper respiratory tract infection a 36 1 Pneumonia a 14 8 Lower respiratory tract infection a 11 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 29 2 Arthralgia 12 < 1 Nervous system disorders Headache 18 < 1 Dizziness a 14 0 Respiratory , thoracic , and mediastinal disorders Cough a 22 0 Dyspnea a 13 1 Skin and subcutaneous tissue disorders Rash a 18 < 1 Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0 . a Includes multiple adverse reaction terms . Laboratory Abnormalities Table 4 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline . The most common (> 5 %) grade 4 laboratory abnormalities observed with VENCLEXTA monotherapy were hematologic laboratory abnormalities , including neutropenia ( 33 %), leukopenia ( 11 %), thrombocytopenia ( 15 %), and lymphopenia ( 9 %). Table 4 . New or Worsening Laboratory Abnormalities with VENCLEXTA Monotherapy ( ≥40 % Any Grade or ≥10 % Grade 3 or 4 ) Laboratory Abnormality All Grades a (%) N = 352 Grade 3 or 4 (%) N = 352 Hematology Leukopenia 89 42 Neutropenia 87 63 Laboratory Abnormality All Grades a (%) N = 352 Grade 3 or 4 (%) N = 352 Hematology Lymphopenia 74 40 Anemia 71 26 Thrombocytopenia 64 31 Chemistry Hypocalcemia 87 12 Hyperglycemia 67 7 Hyperkalemia 59 5 AST increased 53 3 Albumin decreased 49 2 Hypophosphatemia 45 11 Hyponatremia 40 9 a Includes laboratory abnormalities that were new or worsening , or worsening from baseline unknown . Important Adverse Reactions Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA . MURANO In the open-label randomized phase 3 study , the incidence of TLS was 3 % ( 6 / 194 ) in patients treated with VEN + R . After 77 / 389 patients were enrolled in the study , the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures [ see Dosage and Administration ( 2.1 , 2.2 ) in the Full Prescribing Information ]. All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days . All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA . No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures [ see Dosage and Administration ( 2.1 , 2.2 ) in the Full Prescribing Information ]. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN + R are presented in Table 2 . Monotherapy Studies ( M13-982 and M14-032 ) In 168 patients with CLL treated according to recommendations [ see Dosage and Administration ( 2.1 , 2.2 ) in the Full Prescribing Information ], the rate of TLS was 2 %. 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 and / or ALC ≥25 x 109 / L . All events resolved within 5 days . 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 were hyperkalemia ( 17 % all Grades , 1 % Grade ≥3 ), hyperphosphatemia ( 14 % all Grades , 2 % Grade ≥3 ), hypocalcemia ( 16 % all Grades , 2 % Grade ≥3 ), and hyperuricemia ( 10 % all Grades , < 1 % Grade ≥3 ). In the initial Phase 1 dose-finding trials , which had shorter ( 2-3 week ) ramp-up phase and higher starting doses , 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 . After this experience , TLS risk assessment , dosing regimen , TLS prophylaxis and monitoring measures were revised [ see Dosage and Administration ( 2.1 , 2.2 ) in the Full Prescribing Information ]. 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 [ see Dosage and Administration ( 2.3 , 2.4 ) in the Full Prescribing Information ]. Co-administration of ketoconazole increased venetoclax Cmax 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 must be used , reduce the VENCLEXTA dose by at least 50 %. Monitor patients more closely for signs of VENCLEXTA toxicities [ see Dosage and Administration ( 2.3 , 2.4 ) in the Full Prescribing Information ]. 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 [ see Dosage and Administration ( 2.4 ) in the Full Prescribing Information ]. 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 C max 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 C max 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 data on VENCLEXTA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage . 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown . All pregnancies have a background risk of birth defect , loss , or other adverse outcomes . 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 a breastfed child 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 Conduct pregnancy testing in females of reproductive potential 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 352 patients with previously treated CLL evaluated for safety from 3 openlabel trials of VENCLEXTA monotherapy , 57 % ( 201 / 352 ) were ≥65 years of age and 18 % ( 62 / 352 ) were ≥75 years of age . No overall differences in safety and effectiveness were observed between older and younger patients in MURANO and the monotherapy studies . 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 [ see Dosage and Administration ( 2.2 , 2.3 ) in the Full Prescribing Information ]. No specific clinical trials have been conducted in subjects with renal impairment . 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 . No dose adjustment is recommended in patients with mild or moderate hepatic impairment based on results of the population pharmacokinetic analysis ; 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 . OVERDOSAGE There is no specific antidote for VENCLEXTA . For patients who experience overdose , closely monitor and provide appropriate supportive treatment ; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities [ see Dosage and Administration ( 2.2 , 2.3 ) in the Full Prescribing Information ]. Based on venetoclax large volume of distribution and extensive protein binding , dialysis is unlikely to result in significant removal of venetoclax . PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). • Tumor Lysis Syndrome Advise patients of the potential risk of TLS , particularly at treatment initiation and during ramp-up phase , and to immediately report any signs and symptoms associated with this event ( fever , chills , nausea , vomiting , confusion , shortness of breath , seizure , irregular heartbeat , dark or cloudy urine , unusual tiredness , muscle pain , and / or joint discomfort ) to their health care provider ( HCP ) for evaluation [ see Warnings and Precautions ]. Advise patients to be adequately hydrated every day when taking VENCLEXTA to reduce the risk of TLS . The recommended volume is 6 to 8 glasses ( approximately 56 ounces total ) of water each day . Patients should drink water starting 2 days before and on the day of the first dose , and every time the dose is increased . Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [ see Dosage and Administration ( 2.2 ) in the Full Prescribing Information ]. Advise patients that it may be necessary to take VENCLEXTA in the hospital or medical office setting to allow monitoring for TLS . • Neutropenia Advise patients to contact their HCP immediately if they develop a fever or any signs of infection . Advise patients of the need for periodic monitoring of blood counts [ see Warnings and Precautions ]. • Drug Interactions Advise patients to avoid consuming grapefruit products , Seville oranges , or starfruit during treatment with VENCLEXTA . Advise patients that VENCLEXTA may interact with some drugs ; therefore , advise patients to inform their HCP of the use of any prescription medication , over-the-counter drugs , vitamins and herbal products [ see Contraindications and Drug Interactions ]. • Immunizations Advise patients to avoid vaccination with live vaccines because they may not be safe or effective during treatment with VENCLEXTA [ see Warnings and Precautions ]. • Pregnancy and Lactation Advise women of the potential risk to the fetus and to avoid pregnancy during treatment with VENCLEXTA . Advise female patients of reproductive potential to use effective contraception during therapy and for at least 30 days after completing of therapy . Advise females to contact their HCP if they become pregnant , or if pregnancy is suspected , during treatment with VENCLEXTA . Also advise patients not to breastfeed while taking VENCLEXTA [ see Warnings and Precautions , and Use in Specific Populations ]. • Male Infertility Advise patients of the possibility of infertility and possible use of sperm banking for males of reproductive potential [ see Use in Specific Populations ]. Instructions for Taking VENCLEXTA Advise patients to take VENCLEXTA exactly as prescribed and not to change their dose or to stop taking VENCLEXTA unless they are told to do so by their HCP . Advise patients to take VENCLEXTA orally once daily , at approximately the same time each day , according to their HCP ’ s instructions and that the tablets should be swallowed whole with a meal and water without being chewed , crushed , or broken [ see Dosage and Administration ( 2.1 ) in the Full Prescribing Information ]. Advise patients to keep VENCLEXTA in the original packaging during the first 4 weeks of treatment , and not to transfer the tablets to a different container . Advise patients that if a dose of VENCLEXTA is missed by less than 8 hours , to take the missed dose right away and take the next dose as usual . If a dose of VENCLEXTA is missed by more than 8 hours , advise patients to wait and take the next dose at the usual time . Advise patients not to take any additional dose that day if they vomit after taking VENCLEXTA , and to take the next dose at the usual time the following day . Manufactured and Marketed by : AbbVie Inc . North Chicago , IL 60064 and Marketed by : Genentech USA , Inc . A Member of the Roche Group South San Francisco , CA 94080-4990 © 2018 AbbVie Inc . © 2018 Genentech , Inc . Ref : 03-B680 Revised June 2018 750-1952443 MASTER 750-1941834 Print-only content