Venetoclax

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Venclexta: 10 mg, 50 mg, 100 mg

Tablet Therapy Pack, Oral:

Venclexta Starting Pack: Week 1: 10 mg (14); Week 2: 50 mg (7); Week 3: 100 mg (7); Week 4: 100 mg (14) (42 ea)

Pharmacology

Mechanism of Action

Venetoclax has cytotoxic activity in tumor cells which overexpress BCL-2. Venetoclax selectively inhibits the anti-apoptotic protein BCL-2, which is overexpressed in chronic lymphocytic leukemia (CLL) cells and acute myeloid leukemia (AML) cells. BCL-2 mediates tumor cell survival and has been associated with chemotherapy resistance. Venetoclax binds directly to the BCL-2 protein, displacing pro-apoptotic proteins and restoring the apoptotic process.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 256 to 321 L

Metabolism

Hepatic, predominantly via CYP3A; the major metabolite is M27 (has BCL-2 inhibitory activity)

Excretion

Feces (>99.9%; ~21% as unchanged drug); Urine (<0.1%)

Time to Peak

5 to 8 hours

Half-Life Elimination

~26 hours

Protein Binding

Highly bound to plasma proteins

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Following a single 50 mg venetoclax dose, systemic exposure (AUC_inf) was 2.7-fold higher in subjects with severe impairment (Child-Pugh class C), compared to subjects with normal hepatic function.

Use: Labeled Indications

Acute myeloid leukemia: Treatment of newly-diagnosed acute myeloid leukemia (in combination with azacitidine, decitabine, or low-dose cytarabine) in patients ≥75 years of age, or in patients with comorbidities that preclude use of intensive induction chemotherapy

Chronic lymphocytic leukemia/small lymphocytic lymphoma: Treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma in adults

Use: Off Label

Mantle cell lymphoma, relapsed/refractoryb

Data from a phase II trial support the use of venetoclax (in combination with ibrutinib) for the treatment of relapsed or refractory mantle cell lymphoma Tam 2018. Data from a phase I trial and a small retrospective study suggest that venetoclax (as monotherapy) may be of benefit for the treatment of relapsed or refractory mantle cell lymphoma Davids 2017, Davids 2018, Eyre 2019.

Contraindications

Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) due to the potential for increased risk of tumor lysis syndrome.

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to venetoclax or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Assess risk for tumor lysis syndrome (TLS); administer prophylactic hydration and antihyperuricemics prior to the first venetoclax dose (see Premedications). The ramp-up schedule/dose varies by indication.

Acute myeloid leukemia, newly diagnosed: Adults ≥75 years of age or with comorbidities: Oral: Note: Initiate azacitidine, decitabine, or low-dose cytarabine on day 1. The venetoclax dose depends upon the concomitant chemotherapy agent. WBC should be <25,000/mm³ prior to initiation of venetoclax; cytoreduction prior to treatment may be required.

Day 1: 100 mg once daily.

Day 2: 200 mg once daily.

Day 3: 400 mg once daily.

Venetoclax in combination with azacitidine or decitabine: Day 4 and beyond: 400 mg once daily until disease progression or unacceptable toxicity occurs (DiNardo 2019).

Venetoclax in combination with low-dose cytarabine: Day 4 and beyond: 600 mg once daily until disease progression or unacceptable toxicity occurs (Wei 2019).

Chronic lymphocytic leukemia/small lymphocytic lymphoma: Oral:

Week 1: 20 mg once daily.

Week 2: 50 mg once daily.

Week 3: 100 mg once daily.

Week 4: 200 mg once daily.

Week 5: 400 mg once daily.

Venetoclax monotherapy: Week 5 and thereafter: 400 mg once daily; continue until disease progression or unacceptable toxicity occurs.

Venetoclax in combination with obinutuzumab: Note: Obinutuzumab begins on day 1 of cycle 1; initiate venetoclax on day 22 of cycle 1 according to the 5-week ramp-up schedule for chronic lymphocytic leukemia/small lymphocytic lymphoma above; ramp-up will be completed at the end of cycle 2. Cycle 3 (day 1 and beyond): 400 mg once daily until the end of cycle 12. Each cycle is 28 days (Fischer 2019).

Venetoclax in combination with rituximab: Week 5 and thereafter: 400 mg once daily; continue venetoclax until disease progression or unacceptable toxicity occurs, for up to 24 months from day 1 (cycle 1) of rituximab; begin rituximab after receiving venetoclax at the 400 mg once daily dose for 7 days (Seymour 2018).

Premedication: Hydration and antihyperuricemic therapy based on TLS risk:

Acute myeloid leukemia:

WBC should be <25,000/mm³ prior to venetoclax initiation; pre-treatment cytoreduction may be required. Administer adequate hydration and anti-hyperuricemic agents; continue during the ramp-up phase. Correct preexisting electrolyte abnormalities (potassium, uric acid, phosphorus, calcium, and creatinine) prior to venetoclax initiation. For patients at high risk of TLS (eg, circulating blasts, high leukemia burden in the bone marrow, elevated pretreatment lactate dehydrogenase levels, or reduced renal function), additional TLS preventative measures should be considered, including increased laboratory monitoring and reduced initial venetoclax doses.

Chronic lymphocytic leukemia/small lymphocytic lymphoma:

Low tumor burden (all lymph nodes <5 cm and absolute lymphocyte count [ALC] <25,000/mm³): Outpatient: Hydrate with 1.5 to 2 L of oral hydration and administer allopurinol (beginning 2 to 3 days prior to venetoclax initiation). Administer IV hydration for patients unable to tolerate oral hydration.

Medium tumor burden (any lymph node 5 to <10 cm or ALC ≥25,000/mm³): Outpatient: Hydrate with 1.5 to 2 L of oral hydration (administer IV hydration for patients unable to tolerate oral hydration; consider additional IV hydration) and administer allopurinol (beginning 2 to 3 days prior to venetoclax initiation).

High tumor burden (any lymph node ≥10 cm OR ALC ≥25,000/mm³ and any lymph node ≥5 cm): Inpatient: Hydrate with 1.5 to 2 L of oral hydration (administer IV hydration for patients unable to tolerate oral hydration) and 150 to 200 mL/hour IV hydration as tolerated; administer allopurinol (beginning 2 to 3 days prior to venetoclax initiation); consider rasburicase if baseline uric acid is elevated. Ramp-up may be completed outpatient if clinically indicated.

Mantle cell lymphoma, relapsed/refractory (off-label use): Oral:

Venetoclax monotherapy: Initial: 20 mg once daily for week 1, followed by 50 mg once daily for week 2, followed by 100 mg once daily for week 3, followed by 200 mg once daily for week 4, followed by 400 mg once daily for week 5. Week 6 and thereafter: 800 mg once daily until disease progression or unacceptable toxicity occurs or until proceeding to allogeneic stem cell transplant (Davids 2017; Davids 2018).

Venetoclax in combination with ibrutinib: Note: Venetoclax is initiated after 4 weeks of ibrutinib monotherapy to reduce the risk of tumor lysis syndrome. Initial: 20 mg once daily for week 5, followed by 50 mg once daily for week 6, followed by 100 mg once daily for week 7, followed by 200 mg once daily for week 8. Week 9 and thereafter: 400 mg once daily; continue until disease progression or unacceptable toxicity occurs. Venetoclax dose may be increased to 800 mg once daily after week 16 if complete response has not occurred (Tam 2018).

Dosage adjustment for concomitant strong or moderate CYP3A inhibitors or P-gp inhibitors:

Acute myeloid leukemia:

Posaconazole: If concomitant administration of posaconazole and venetoclax is required, a reduced ramp-up venetoclax dosing schedule is necessary.

Day 1: 10 mg.

Day 2: 20 mg.

Day 3: 50 mg.

Day 4 and beyond: 70 mg.

For patients who have completed dose escalation and are on a steady daily venetoclax dose, reduce the venetoclax dose to 70 mg once daily when posaconazole must be used concurrently.

Strong CYP3A inhibitors (other than posaconazole): If concomitant administration of a strong CYP3A inhibitor (other than posaconazole) and venetoclax is required, a reduced ramp-up venetoclax dosing schedule is necessary.

Day 1: 10 mg.

Day 2: 20 mg.

Day 3: 50 mg.

Day 4 and beyond: 100 mg.

For patients who have completed dose escalation and are on a steady daily venetoclax dose, reduce the venetoclax dose to 100 mg once daily when a strong CYP3A inhibitor (other than posaconazole) must be used concurrently.

Moderate CYP3A inhibitors and P-gp inhibitors: Reduce the venetoclax dose by at least 50%.

Following discontinuation of the CYP3A or P-gp inhibitor: 2 to 3 days after the inhibitor is discontinued, resume the venetoclax dose that was used prior to initiating the CYP3A or P-gp inhibitor.

Chronic lymphocytic leukemia/small lymphocytic lymphoma:

Posaconazole: The concomitant use of posaconazole is contraindicated at initiation of venetoclax and during dose escalation. For patients who have completed dose escalation and are on a steady daily venetoclax dose, either consider use of an alternative agent or reduce the venetoclax dose to 70 mg once daily when posaconazole must be used concurrently.

Strong CYP3A inhibitors (other than posaconazole): The use of strong CYP3A inhibitors is contraindicated at initiation of venetoclax and during dose escalation. For patients who have completed dose escalation and are on a steady daily venetoclax dose, either consider use of an alternative agent or reduce the venetoclax dose to 100 mg once daily when a strong CYP3A inhibitor (other than posaconazole) must be used concurrently.

Moderate CYP3A inhibitors and P-gp inhibitors: Consider use of an alternative agent or reduce the venetoclax dose by at least 50%.

Following discontinuation of the CYP3A or P-gp inhibitor: 2 to 3 days after the inhibitor is discontinued, resume the venetoclax dose that was used prior to initiating the CYP3A or P-gp inhibitor.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Acute myeloid leukemia: Note: Monitor blood counts frequently until cytopenias resolve. Toxicity may require venetoclax dose interruptions or permanent discontinuation.

Grade 4 neutropenia (with or without fever or infection) or grade 4 thrombocytopenia:

Occurring prior to achieving remission: Transfuse blood products, administer prophylactic and treatment anti-infectives as clinically necessary. In most instances, treatment cycles (of venetoclax and azacitidine, decitabine, or low-dose cytarabine) should not be interrupted due to cytopenias (prior to achieving remission).

First occurrence after achieving remission and lasting at least 7 days: Delay subsequent treatment cycle (of venetoclax and azacitidine, decitabine, or low-dose cytarabine) and monitor blood counts. Administer granulocyte-colony stimulating factors (G-CSFs) if clinically indicated for neutropenia; once neutropenia has resolved to ≤ grade 2, resume venetoclax at the same dose in combination with azacitidine, decitabine, or low-dose cytarabine.

Subsequent occurrences in cycles after achieving remission and lasting 7 days or longer: Delay subsequent treatment cycle (of venetoclax and azacitidine, decitabine, or low-dose cytarabine) and monitor blood counts. Administer G-CSFs if clinically indicated for neutropenia; once neutropenia has resolved to ≤ grade 2, resume venetoclax at the same dose and the duration reduced by 7 days for each subsequent cycle.

Chronic lymphocytic leukemia/small lymphocytic lymphoma:

Interrupt or reduce dose for toxicities. Reassess risk for tumor lysis syndrome in patients who have had an interruption in dosing of >1 week during the first 5 weeks or >2 weeks at 400 mg once daily (to determine if re-initiation with a reduced dose is necessary).

Table has been converted to the following text:

Dose Reduction Levels for Venetoclax Toxicity in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

If the dose at interruption was 400 mg once daily, restart at 300 mg.

If the dose at interruption was 300 mg once daily, restart at 200 mg.

If the dose at interruption was 200 mg once daily, restart at 100 mg.

If the dose at interruption was 100 mg once daily, restart at 50 mg.

If the dose at interruption was 50 mg once daily, restart at 20 mg.

If the dose at interruption was 20 mg once daily, restart at 10 mg.

Note: During dose escalation phase, continue the reduced dose for 1 week prior to increasing the dose. Consider discontinuation for patients who require dose reductions to less than 100 mg for more than 2 weeks.

Tumor lysis syndrome:

Blood chemistry changes or symptoms suggestive of tumor lysis syndrome (TLS): Withhold the next day's dose.

If resolved within 24 to 48 hours of the last dose: Resume at the same dose.

If blood chemistry changes require more than 48 hours to resolve: Resume at a reduced dose.

Clinical TLS (laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, and/or seizure): Withhold dose; following resolution, resume at a reduced dose.

Hematologic toxicity: Grade 3 neutropenia with infection or fever or grade 4 hematologic toxicities (except lymphopenia):

First occurrence: Interrupt treatment. May administer granulocyte-colony stimulating factors (G-CSFs) with venetoclax to reduce infection risk associated with neutropenia. May resume at the same dose once toxicity is resolved to grade 1 or baseline.

Second and subsequent occurrences: Interrupt treatment. Consider G-CSFs as clinically indicated. Resume at a lower dose level once toxicity is resolved (see dosage reduction levels in above table; a larger dose reduction may be necessary based on clinical discretion).

Nonhematologic toxicities, Grade 3 or 4 toxicity:

First occurrence: Interrupt treatment. May resume at the same dose once toxicity is resolved to grade 1 or baseline (no dosage adjustment is necessary).

Second and subsequent occurrences: Interrupt treatment. Resume at a lower dose level once toxicity is resolved (see dosage reduction levels in above table; a larger dose reduction may be necessary based on clinical discretion).

Administration

Oral: Administer with a meal and water at approximately the same time each day. Swallow whole; do not crush, chew, or break prior to administration.

Missed or vomited doses: If a dose is missed and it is within 8 hours of the missed usual dosing time, administer the missed dose as soon as possible and resume the normal daily dosing schedule. If it is more than 8 hours, do not administer the missed dose and resume the usual dosing schedule the next day. If the patient vomits following administration of a dose, no additional doses should be administered that day; the next prescribed dose should be taken at the usual time.

Dietary Considerations

Administration with a low-fat meal increased exposure by ~3.4 fold and administration with a high-fat meal increased exposure by ~5.1 to 5.3 fold, compared to fasting. Avoid grapefruit products, Seville oranges, and Star Fruit.

Storage

Store at or below 30°C (86°F).

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bitter Orange: May increase the serum concentration of Venetoclax. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Venetoclax. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Venetoclax. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Venetoclax. Management: This combination is contraindicated during venetoclax initiation and ramp-up in patients with CLL/SLL. Reduced venetoclax doses are required during ramp-up for patients with AML, and reduced doses are required for all patients during maintenance therapy. Exceptions: Posaconazole. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Digoxin: Venetoclax may increase the serum concentration of Digoxin. Management: Administer digoxin at least 6 hours before venetoclax when concomitant therapy is required. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Everolimus: Venetoclax may increase the serum concentration of Everolimus. Management: Administer everolimus at least 6 hours before venetoclax when concomitant therapy is required. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Venetoclax. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Exceptions: Azithromycin (Systemic). Consider therapy modification

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Posaconazole: May increase the serum concentration of Venetoclax. Management: This combination is contraindicated during venetoclax initiation and ramp-up in patients with CLL/SLL. Reduced venetoclax doses are required during ramp-up for patients with AML, and reduced doses are required for all patients during maintenance therapy. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sirolimus: Venetoclax may increase the serum concentration of Sirolimus. Management: Administer sirolimus at least 6 hours before venetoclax when concomitant therapy is required. Consider therapy modification

Star Fruit: May increase the serum concentration of Venetoclax. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Vaccines (Inactivated): Venetoclax may diminish the therapeutic effect of Vaccines (Inactivated). Monitor therapy

Vaccines (Live): Venetoclax may enhance the adverse/toxic effect of Vaccines (Live). Venetoclax may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live, attenuated vaccines before, during, or after (prior to B-cell recovery) venetoclax treatment. Avoid combination

Warfarin: Venetoclax may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (22%)

Central nervous system: Fatigue (32%), headache (18%), dizziness (14%)

Dermatologic: Skin rash (18%)

Endocrine & metabolic: Hypocalcemia (16% to 87%), hyperglycemia (67%), hyperkalemia (17% to 59%), decreased serum albumin (49%), hypophosphatemia (45%), hyponatremia (40%), hyperphosphatemia (14%)

Gastrointestinal: Diarrhea (43%), nausea (42%), abdominal pain (18%), constipation (16%), vomiting (16%), stomatitis (13%)

Hematologic & oncologic: Leukopenia (89%; grades 3/4: 42%; grade 4: 11%), neutropenia (50% to 87%; ≥ grade 3: 45% to 63%; grade 4: 33%), lymphocytopenia (11% to 74%; ≥ grade 3: 7% to 40%; grade 4: 9%), anemia (33% to 71%; ≥ grade 3: 18% to 26%), thrombocytopenia (29% to 64%; ≥ grade 3: 20% to 31%; grade 4: 15%), tumor lysis syndrome (2 to 3 week ramp-up phase: 13%; 5 week ramp-up phase: 2%)

Hepatic: Increased serum aspartate aminotransferase (53%)

Neuromuscular & skeletal: Musculoskeletal pain (29%), arthralgia (12%)

Respiratory: Upper respiratory tract infection (36%), cough (22%), pneumonia (14%), dyspnea (13%), lower respiratory tract infection (11%)

Miscellaneous: Fever (18%)

1% to 10%:

Endocrine & metabolic: Hyperuricemia (10%)

Hematologic & oncologic: Febrile neutropenia (6%; ≥ grade 3: 6%)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia, thrombocytopenia, and anemia may occur. Grade 3 and 4 neutropenia commonly occurred in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients receiving venetoclax, either as monotherapy or in combination with rituximab or obinutuzumab. Neutropenic fever has been reported both with monotherapy and combination therapy. When used in combination with azacitidine, decitabine, or low-dose cytarabine for acute myeloid leukemia (AML), baseline neutrophil counts worsened in almost all patients; neutropenia may occur with subsequent cycles. Monitor CBC with differential throughout treatment. May require treatment interruption and/or dose reduction. Consider antimicrobials and WBC growth factor support as clinically indicated.
• Infection: Serious and fatal infections, including pneumonia and sepsis, have occurred. Monitor closely for signs/symptoms of infection and manage promptly. Interrupt venetoclax therapy for grade 3 or higher infection.
• Tumor lysis syndrome: Tumor lysis syndrome (TLS; including fatalities and renal failure requiring dialysis), has occurred in patients with high tumor burden when treated with venetoclax. Venetoclax may cause a rapid reduction in tumor volume and therefore a risk for TLS is present during initiation and during the ramp-up phase of treatment. The use of the ramp-up dose, TLS prophylaxis, and monitoring has reduced the rate of TLS in venetoclax monotherapy studies; a shorter ramp up (eg, 2 to 3 weeks) and higher initial doses have resulted in higher rates of TLS and related complications in patients with CLL/SLL. Changes in blood chemistries consistent with TLS may occur as early as 6 to 8 hours after the first dose and with dose increases, and require prompt management. The risk for TLS is increased with high tumor burden and comorbidities; reduced renal function further increases TLS risk. Assess risk for TLS; initiate appropriate TLS prophylactic management (eg, hydration and antihyperuricemic therapy); monitor blood chemistries closely and manage abnormalities promptly. May require treatment interruption and dose reduction. The risk for TLS may decrease as tumor burden decreases. Utilize more intensive measures (IV hydration, frequent monitoring, hospitalization) as the overall TLS risk increases. Concomitant use of strong or moderate CYP3A inhibitors or P-gp inhibitors at initiation or during ramp-up may increase the risk for TLS and requires venetoclax dosage modification.

Disease related concerns:

• Hepatic impairment: Dosage adjustment recommended in patients with severe hepatic impairment. Monitor closely for toxicities.
• Multiple myeloma: In patients with relapsed or refractory multiple myeloma, an increase in mortality was noted when venetoclax was added to bortezomib and dexamethasone. Venetoclax is not approved for the treatment of multiple myeloma.
• Renal impairment: Patients with decreased renal function (CrCl <80 mL/minute) are at increased risk for TLS and may require more intensive TLS prophylaxis and monitoring during treatment initiation and dose escalation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Immunizations: Live vaccinations should not be administered prior to, during, or after venetoclax treatment until B-cell recovery occurs. Vaccines may be less effective.

Monitoring Parameters

CBC with differential (throughout treatment); blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); pregnancy test (prior to treatment in females of reproductive potential); assess tumor burden, including radiographic evaluation (eg, CT scan) for tumor lysis syndrome (TLS) risk evaluation; monitor for signs/symptoms of infection. Monitor adherence.

Blood chemistry monitoring in acute myeloid leukemia: Assess and correct pre-existing abnormalities prior to therapy initiation; monitor blood chemistries for TLS prior to first dose, 6 to 8 hours after each new dose during ramp-up, and 24 hours after reaching the final dose. Increased monitoring may be necessary in patients at high risk for TLS.

Blood chemistry monitoring based on tumor burden/TLS risk in chronic lymphocytic leukemia/small lymphocytic lymphoma:

Low risk (all lymph node <5 cm and absolute lymphocyte count [ALC] <25,000/mm³) or medium risk (any lymph node 5 to <10 cm or ALC ≥25,000/mm³): Prior to first dose, 6 to 8 hours, and 24 hours after first 20 mg and 50 mg dose, and prior to each subsequent initial ramp up dose.

High risk (any lymph node ≥10 cm OR ALC ≥25,000/mm³ and any lymph node ≥5 cm): Prior to first dose, 4, 8, 12, and 24 hours after first 20 mg and 50 mg dose, and prior to plus 6 to 8 hours and 24 hours after each subsequent initial ramp up dose.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, venetoclax is expected to cause fetal harm if administered during pregnancy.

Females of reproductive potential should have a pregnancy test prior to therapy and use effective contraception during treatment and for at least 30 days after the final dose.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.
• It is used to treat a type of lymphoma.

Frequently reported side effects of this drug

• Abdominal pain
• Common cold symptoms
• Fatigue
• Muscle pain
• Joint pain
• Back pain
• Constipation
• Trouble sleeping
• Mouth irritation
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Severe headache
• Dizziness
• Passing out
• Vision changes
• Severe loss of strength and energy
• Pale skin
• Bruising
• Bleeding
• Swelling
• Shortness of breath
• Urine discoloration
• Dark urine
• Yellow skin or eyes
• Severe diarrhea
• Severe nausea
• Vomiting
• Not able to eat
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.