Venclexta: Indications, Dosage, Precautions, Adverse Effects
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Venclexta - Product Information

Manufacture: AbbVie
Country: United States
Condition: Chronic Lymphocytic Leukemia
Class: Miscellaneous antineoplastics
Form: Tablets
Ingredients: Venetoclax, Copovidone, Colloidal silicon dioxide, Polysorbate 80, Sodium stearyl fumarate, Calcium phosphate dibasic.

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.

Dosage and Administration

Patient Selection

Select patients for the treatment of relapsed or refractory CLL with VENCLEXTA based on the presence of 17p deletions in blood specimens [see Indications and Usage]. Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur. Information on FDA-approved tests for the detection of 17p deletions in CLL is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to reduce risk of TLS [see Dosage and Administration and Warnings and Precautions]. Administer the VENCLEXTA dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.

Instruct patients to take VENCLEXTA tablets with a meal and water at approximately the same time each day. VENCLEXTA tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Table 1. Dosing Schedule for Ramp-Up Phase
Week VENCLEXTA Daily Dose
1 20 mg
2 50 mg
3 100 mg
4 200 mg
5 and beyond 400 mg

The Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule. Once the ramp- up phase is completed, the 400 mg dose is achieved using 100 mg tablets supplied in bottles [see How Supplied/Storage and Handling].

VENCLEXTA should be taken orally once daily until disease progression or unacceptable toxicity is observed.

Risk Assessment and Prophylaxis for Tumor Lysis Syndrome

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. Perform tumor burden assessments, including radiographic evaluation (e.g., CT scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA. Reduced renal function (creatinine clearance [CrCl] <80 mL/min) further increases the risk. The risk may decrease as tumor burden decreases [see Warnings and Precautions and Use in Specific Populations].

Table 2 below describes the recommended TLS prophylaxis and monitoring during VENCLEXTA treatment based on tumor burden determination from clinical trial data.

Table 2. Recommended TLS Prophylaxis Based on Tumor Burden From Clinical Trial Data (consider all patient co-morbidities before final determination of prophylaxis and monitoring schedule)
Tumor  Burden                Prophylaxis Blood Chemistry Monitoringc,d
Hydrationa Anti-hyperuricemics Setting and Frequency of Assessments
Low All LN <5 cm AND
ALC <25 x109/L
Oral (1.5-2 L) Allopurinolb Outpatient
   •  Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg
   •  Pre-dose at subsequent ramp-up doses
 
Medium Any LN 5 cm to <10 cm OR
ALC ≥25 x109/L
Oral (1.5-2L) and consider additional intravenous Allopurinol Outpatient
   •  Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg
   •  Pre-dose at subsequent ramp-up doses
   •  Consider hospitalization for patients with CrCl <80ml/min at first dose of 20 mg and 50 mg; see below for monitoring in hospital
High Any LN ≥10 cm OR
ALC ≥25 x109/L
AND any LN ≥5 cm
Oral (1.5-2L) and intravenous (150-200mL/hr as tolerated) Allopurinol; conside rasburicase if baseline uric acid is elevated In hospital at first dose of 20 mg and 50 mg
   •  Pre-dose, 4, 8,12 and 24 hours
Outpatient at subsequent ramp-up doses
   •  Pre-dose, 6 to 8 hours, 24 hours

ALC = absolute lymphocyte count; LN = lymph node.

aAdminister intravenous hydration for any patient who cannot tolerate oral hydration.

bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA.

cEvaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.

dFor patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose.

Dose Modifications Based on Toxicities

Interrupt dosing or reduce dose for toxicities. See Table 3 for dose modifications for hematologic and other toxicities related to VENCLEXTA, and Table 4 for dose. For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks when at the daily dose of 400 mg, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule) [see Dosage and Administration].

Table 3. Recommended Dose Modifications for Toxicitiesa
Event Occurrence Action
Tumor Lysis Syndrome
Blood chemistry changes or symptoms suggestive of TLS Any Withhold the next day’s dose. If resolvedithin 24 to 48 hours of last dose, resume at theame dose.
For any blood chemistry changes requiringore than 48 hours to resolve, resume at aeduced dose (see Table 4) [see Dosage and Administration].
For any events of clinical TLS,b resume at aeduced dose following resolution (see Table 4)[see Dosage and Administration].
Non-Hematologic Toxicities
Grade 3 or 4 non-hematologic toxicities 1st occurrence Interrupt VENCLEXTA.
Once the toxicity has resolved to Grade 1 or baseline level, VENCLEXTA therapy may be resumed at the same dose. No dose modification is required.
2nd and subsequent occurrences Interrupt VENCLEXTA.
Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTAafter resolution. A larger dose reduction mayoccur at the discretion of the physician.
Hematologic Toxicities
Grade 3 or 4neutropenia withinfection or fever; orGrade 4 hematologictoxicities (exceptlymphopenia) [see Warnings and Precautions] 1st occurrence Interrupt VENCLEXTA. To reduce the infection risks associated withneutropenia, granulocyte-colony stimulatingfactor (G-CSF) may be administered withVENCLEXTA if clinically indicated. Once thetoxicity has resolved to Grade 1 or baselinelevel, VENCLEXTA therapy may be resumedat the same dose.
2nd and subsequent occurrences Interrupt VENCLEXTA.
Consider using G-CSF as clinically indicated. Follow dose reduction guidelines in Table 4when resuming treatment with VENCLEXTAafter resolution. A larger dose reduction mayoccur at the discretion of the physician.

Consider discontinuing VENCLEXTA for patients who require dose reductions to less than 100 mg for more than 2 weeks.

aAdverse reactions were graded using NCI CTCAE version 4.0.

bClinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures.

Table 4. Dose Modification for Toxicity During VENCLEXTA Treatment
Dose at Interruption, mg Restart Dose, mga
400 300
300 200
200 100
100 50
50 20
20 10

aDuring the ramp-up phase, continue the reduced dose for 1 week before increasing the dose.

Dose Modifications for Use with CYP3A and P-gp Inhibitors

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. Concomitant use of VENCLEXTA with strong CYP3A inhibitors increases venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during ramp-up phase [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 strong CYP3A inhibitors must be used concomitantly.

Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors or P-gp inhibitors. 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 these patients more closely for signs of toxicities [see Dosage and Administration].

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 and Drug Interactions].

The recommendations for managing drug-drug interactions are summarized in Table 5.

Table 5. Management of Potential VENCLEXTA Interactions with CYP3A and P-gp Inhibitors
Inhibitors Initiation and Ramp-Up Phase Steady Daily Dose (After Ramp-Up Phase)
Strong CYP3A inhibitor Contraindicated Avoid inhibitor use or reducehe VENCLEXTA dose by at least 75%
Moderate CYP3A inhibitor Avoid inhibitor use or reduce the VENCLEXTA dose by ateast 50%
P-gp inhibitor

Missed Dose

If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the next day.

If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time.

Dosage Forms and Strengths

Table 6. VENCLEXTA Tablet Strength and Description
Tablet Strength Description of Tablet
10 mg Round, biconvex shaped, pale yellow film-coated tablet debossed with “V” on one side and “10” on the other side
50 mg Oblong, biconvex shaped, beige film-coated tablet debossed with “V” on one side and “50” on the other side
100 mg Oblong, biconvex shaped, pale yellow film-coated tablet debossed with “V” on one side and “100” on the other side

Contraindications

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated [see Dosage and Administration and 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 (see Table 2) 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 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 and 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) [see Dosage and Administration].

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 7.

Table 7. Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3 or 4) of Patients with CLL
Body System Adverse Reaction Any Grade (%) N=240 Grade 3 or 4 (%) N=240
Blood and lymphatic system disorders Neutropeniaa 45 41
Anemiab 29 18
Thrombocytopeniac 22 15
Febrile neutropenia 5 5
Gastrointestinal disorders Diarrhea 35 <1
Nausea 33 <1
Vomiting 15 <1
Constipation 14 0
General disorders and administration site conditions Fatigue 21 2
Pyrexia 16 <1
Peripheral edema 11 <1
Infections and infestations Upper respiratory tract infection 22 1
Pneumonia 8 5
Metabolic and nutrition disorders Hypokalemia 12 4
Musculoskeletal and connective tissue disorders Back pain 10 <1
Nervous system disorders Headache 15 <1
Respiratory, thoracic, and mediastinal disorders Cough 13 0

Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0.

aNeutropenia/neutrophil count decreased.

bAnemia/hemoglobin decreased.

cThrombocytopenia/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 [see Dosage and Administration]. In venetoclax clinical trials, patients with any measurable lymph node ≥10 cm or those with both an ALC ≥25 x 109/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 109/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 8.

Table 8. Adverse Reactions of TLS and Relevant Laboratory Abnormalities Reported in Patients with CLL
Parameter All Grades (%) N=66 Grade ≥3 (%) N=66
Laboratory TLSa 6 6
Hyperkalemiab 20 2
Hyperphosphatemiac 15 3
Hypocalcemiad 9 3
Hyperuricemiae 6 2

aLaboratory 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.

bHyperkalemia/blood potassium increased

cHyperphosphatemia/blood phosphorus increased

dHypocalcemia/blood calcium decreased.

eHyperuricemia/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 [see Dosage and Administration].

Co-administration of ketoconazole increased venetoclax Cmax 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 [see Dosage and Administration].

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].

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

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

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.

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 [see Dosage and Administration].

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.

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]. Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.

How Supplied/Storage and Handling

VENCLEXTA is dispensed as follows:

Packaging Presentation Number of Tablets National Drug Code (NDC)
Starting Pack Each pack contains four weekly wallet blister packs:
   • Week 1 (14 x 10 mg tablets)
   • Week 2 (7 x 50 mg tablets)
   • Week 3 (7 x 100 mg tablets)
   • Week 4 (14 x 100 mg tablets)
0074-0579-28
10 mg Wallet 14 x 10 mg tablets 0074-0561-14
50 mg Wallet 7 x 50 mg tablets 0074-0566-07
10 mg Unit Dose 2 x 10 mg tablets 0074-0561-11
50 mg Unit Dose 1 x 50 mg tablet 0074-0566-11
100 mg Unit Dose 1 x 100 mg tablet 0074-0576-11
100 mg Bottle 120 x 100 mg tablets 0074-0576-22

VENCLEXTA 10 mg film-coated tablets are round, biconvex shaped, pale yellow debossed with “V” on one side and “10” on the other side.

VENCLEXTA 50 mg film-coated tablets are oblong, biconvex shaped, beige debossed with “V” on one side and “50” on the other side.

VENCLEXTA 100 mg film-coated tablets are oblong, biconvex shaped, pale yellow debossed with “V” on one side and “100” on the other side.

Store at or below 86°F (30°C).

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Consumer Medicine Information).

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 doctor 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 [see Dosage and Administration].

Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Dosage and Administration].

Advise patients that it may be necessary to take VENCLEXTA in the presence of a doctor to allow monitoring for TLS.

Neutropenia

Advise patients to contact their doctor 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 doctor 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 doctor 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 doctor. Advise patients to take VENCLEXTA orally once daily, at approximately the same time each day, according to their doctor’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].

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 [see Dosage and Administration].

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