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Venetoclax

Pronunciation

(ven ET oh klax)

Index Terms

  • ABT-0199
  • ABT-199
  • BCL-2 Inhibitor GDC-0199
  • GDC-0199
  • RG7601

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)

Brand Names: U.S.

  • Venclexta
  • Venclexta Starting Pack

Pharmacologic Category

  • Antineoplastic Agent
  • Antineoplastic Agent, BCL-2 Inhibitor

Pharmacology

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. 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.

Distribution

Vdss: 256 to 321 L

Metabolism

Hepatic, predominantly via CYP3A4/5; 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: Labeled Indications

Chronic lymphocytic leukemia: Treatment of chronic lymphocytic leukemia (CLL) in patients with 17p deletion (as detected by an approved test) who have received at least one prior therapy.

Contraindications

Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase

Dosing: Adult

Note: Assess risk for tumor lysis syndrome (TLS); administer prophylactic hydration and antihyperuricemics.

Chronic lymphocytic leukemia, relapsed/refractory, 17p deletion: Oral: Escalate dose in weekly increments over 5 weeks to reduce the risk of TLS:

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 and thereafter: 400 mg once daily; continue until disease progression or unacceptable toxicity.

Premedications: Hydration and antihyperuricemic therapy based on TLS risk:

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.

Dosage adjustment for concomitant CYP3A4 and P-glycoprotein (P-gp) inhibitors:

Strong CYP3A inhibitors: 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, reduce the venetoclax dose by at least 75% when a strong CYP3A inhibitor must be used concurrently.

Moderate CYP3A inhibitors and P-gp inhibitors: Avoid concomitant use of venetoclax with moderate CYP3A and P-gp inhibitors (consider alternative treatments); if concurrent use cannot be avoided, 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: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary; use with caution due to increased risk for TLS.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

End-stage renal disease (ESRD) requiring dialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Dialysis is unlikely to significantly remove venetoclax (due to large volume of distribution and extensive protein binding).

Dosing: Hepatic Impairment

Mild impairment (normal total bilirubin and AST > upper limit of normal [ULN] or total bilirubin >1 to 1.5 times ULN): No dosage adjustment necessary.

Moderate impairment (total bilirubin >1.5 to 3 times ULN): No dosage adjustment necessary; monitor closely for signs of toxicity.

Severe impairment (total bilirubin >3 times ULN): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

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).

Dose Reduction Levels for Venetoclax Toxicity

Dose at interruption

Restart dosea

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

aDuring dose escalation phase, continue the reduced dose for 1 week prior to increasing the dose.

400 mg

300 mg

300 mg

200 mg

200 mg

100 mg

100 mg

50 mg

50 mg

20 mg

20 mg

10 mg

Table has been converted to the following text:

Dose Reduction Levels for Venetoclax Toxicity

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 (TLS):

Blood chemistry changes or symptoms suggestive of 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 or 4 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.

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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). NIOSH recommends single gloving for administration of an intact tablet (NIOSH 2014).

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.

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

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. 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: These combinations are contraindicated during venetoclax initiation and ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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. Monitor therapy

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

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit 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

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. 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. 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. 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: Peripheral edema (11%; grades 3/4: <1%)

Central nervous system: Fatigue (21%; grades 3/4: 2%), headache (15%; grades 3/4: <1%)

Endocrine & metabolic: Hyperkalemia (20%; ≥ grade 3: 2%), hyperphosphatemia (15%; ≥ grade 3: 3%), hypokalemia (12%; grades 3/4: 4%)

Gastrointestinal: Diarrhea (35%; grades 3/4: <1%), nausea (33%; grades 3/4: <1%), vomiting (15%; grades 3/4: <1%), constipation (14%)

Hematologic & oncologic: Neutropenia (45%; grades 3/4: 41%), anemia (29%; grades 3/4: 18%), thrombocytopenia (22%; grades 3/4: 15%)

Respiratory: Upper respiratory tract infection (22%; grades 3/4: 1%), cough (13%)

Miscellaneous: Fever (16%; grades 3/4: <1%)

1% to 10%

Endocrine & metabolic: Hypocalcemia (9%; ≥ grade 3: 3%), hyperuricemia (6%; ≥ grade 3: 2%)

Hematologic & oncologic: Tumor lysis syndrome (2 to 3 week ramp-up phase: 12%; 5 week ramp-up phase: 6%; ≥ grade 3: 6%), febrile neutropenia (5%; grades 3/4: 5%)

Neuromuscular & skeletal: Back pain (10%; grades 3/4: <1%)

Respiratory: Pneumonia (8%; grades 3/4: 5%)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia, thrombocytopenia, and anemia may occur. Grade 3 and 4 neutropenia occurred in almost half of patients receiving venetoclax. Neutropenic fever has been reported. Monitor CBC with differential throughout treatment. May require treatment interruption and/or dose reduction. Consider antimicrobials and WBC growth factor support as clinically indicated.

• Tumor lysis syndrome: Venetoclax may cause a rapid reduction in tumor volume and therefore a risk for tumor lysis syndrome (TLS) is present during the initial 5-week dose escalation phase of treatment. TLS has occurred with venetoclax in previously treated chronic lymphocytic leukemia (CLL) patients with high tumor burden; renal failure (requiring dialysis) and fatalities have been reported. 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; creatinine clearance <80 mL/minute 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. Patients at high risk for TLS may require hospitalization at treatment initiation. Concomitant use of CYP3A or P-gp inhibitors at initiation or during dose escalation may increase the risk for TLS.

Disease related concerns:

• Hepatic impairment: Adverse events may be increased in patients with moderate impairment; monitor closely for toxicity.

• 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Appropriate use: Select patients for treatment (of relapsed or refractory chronic lymphocytic leukemia) based on the presence of a 17p deletion. Patients without a 17p deletion at diagnosis should be re-tested at relapse as acquisition of 17p deletion may occur. Information on approved tests for 17p deletion detection may be found at http://www.fda.gov/CompanionDiagnostics.

• 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

17p deletion status (prior to treatment initiation or at relapse); pregnancy test (prior to treatment in females of reproductive potential); CBC with differential (throughout treatment); blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); assess tumor burden, including radiographic evaluation (eg, CT scan) for tumor lysis syndrome (TLS) risk evaluation.

Blood chemistry monitoring based on tumor burden/TLS risk:

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 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. Based on animal data, venetoclax may compromise fertility in males.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, nausea, vomiting, nasal irritation, throat irritation, constipation, back pain, or headache. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), severe loss of strength and energy, pale skin, swelling of arms or legs, confusion, shortness of breath, seizures, urine discoloration, dark urine, jaundice, or joint pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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