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Venclexta

Generic Name: Venetoclax
Class: Antineoplastic Agents
Chemical Name: 4 - Dimethyl - 1 - cyclohexen - 1 - yl]methyl] - 1 - piperazinyl] - N - [[3 - nitro - 4 - [[(tetrahydro - 2H - pyran - 4 - yl)methyl]amino]phenyl]sulfonyl] - 2 - (1H - pyrrolo[2,3 - b]pyridin - 5 - yloxy) - benzamide, 4-[4-[[2-(4-chlorophenyl)-4
Molecular Formula: C45H50ClN7O7S
CAS Number: 1257044-40-8

Introduction

Antineoplastic agent; inhibitor of B-cell lymphoma 2 (BCL-2).1 2 7 9 10

Uses for Venclexta

Chronic Lymphocytic Leukemia (CLL)

Treatment of CLL with 17p deletion (as detected by an FDA-approved diagnostic test) in patients who have received at least one prior therapy.1 2

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Designated an orphan drug by FDA for treatment of CLL.3

Venclexta Dosage and Administration

General

  • Confirm presence of 17p deletion chromosomal abnormality with an FDA-approved test (e.g., Vysis fluorescent in situ hybridization [FISH] kit) prior to initiating therapy.1 Because 17p deletion can be acquired, patients without 17p deletion at diagnosis should be retested at relapse.1

  • Prior to initiating therapy, assess patients for risk of tumor lysis syndrome and give appropriate prophylaxis (e.g., adequate hydration and antihyperuricemic agent) based on tumor burden at baseline (see Table 1).1 Consider patient comorbidities and other risk factors when determining appropriate prophylactic regimen.1 (See Tumor Lysis Syndrome under Cautions.)

Administer IV hydration if oral hydration is not tolerated

Begin oral hydration 2 days prior to initiating venetoclax, on the day of the first dose, and every time the dose is increased

Initiate antihyperuricemic agent (e.g., allopurinol) 2–3 days prior to initiating venetoclax

Table 1. Recommended Prophylaxis and Monitoring for Tumor Lysis Syndrome1

Tumor Burden

Prophylaxis

Monitoring

Low tumor burden: All lymph nodes with diameter <5 cm and absolute lymphocyte count <25,000/mm3

Oral hydration (1.5–2 L), and allopurinol

Assess blood chemistries (i.e., potassium, phosphorus, calcium, uric acid, creatinine) prior to, at 6–8 and 24 hours following the first 20- and 50-mg dose of venetoclax, and prior to each subsequent escalating dose (100, 200, and 400 mg)

Medium tumor burden: Any lymph node diameter 5 cm to <10 cm or absolute lymphocyte count ≥25,000/mm3

Oral hydration (1.5–2 L), and allopurinol

Consider additional IV hydration

Assess blood chemistries (i.e., potassium, phosphorus, calcium, uric acid, creatinine) prior to, at 6–8 and 24 hours following the first 20- and 50-mg dose of venetoclax, and prior to each subsequent escalating dose (100, 200, and 400 mg)

In patients with Clcr <80 mL/minute prior to the 20- and 50-mg dose, consider hospitalization for drug administration and more intensive hydration and monitoring (see the following recommendations for monitoring in hospital)

High tumor burden: Any lymph node diameter ≥10 cm or any lymph node diameter ≥5 cm and absolute lymphocyte count ≥25,000/mm3

Oral (1.5–2 L), and IV (150–200 mL/hour as tolerated) hydration and allopurinol

Consider rasburicase if baseline uric acid concentrations are elevated

Hospitalize patients for administration of the first 20- and 50-mg dose of venetoclax; assess blood chemistries (i.e., potassium, phosphorus, calcium, uric acid, creatinine) prior to and at 4, 8, 12, and 24 hours following each dose

Administer subsequent escalating doses (100, 200, and 400 mg) in the outpatient setting; assess blood chemistries prior to and at 6–8 and 24 hours following each dose

Administration

Oral Administration

Administer orally once daily with a meal and full glass of water at approximately the same time each day.1 12 Swallow tablets intact; do not chew, crush, or break.1

Dosage

Adults

CLL
Oral

400 mg once daily; to minimize risk of tumor lysis syndrome, initiate at a low dosage and titrate over 5 weeks according to the following schedule: 20 mg daily in first week, 50 mg daily in second week, 100 mg daily in third week, 200 mg daily in fourth week, then 400 mg daily thereafter.1

Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification for Toxicity
Oral

If a dosage modification is needed, adjust dose by one dose level (i.e., 400 mg to 300 mg; 300 mg to 200 mg; 200 mg to 100 mg; 100 mg to 50 mg; 50 mg to 20 mg; 20 mg to 10 mg).1

If dose reduction occurs during the initial 5-week titration period, continue reduced dose for 1 week before escalating back to previous dose.1 If dose reduction to <100 mg for >2 weeks is necessary, consider discontinuing therapy.1

If interruption of therapy is necessary for >1 week during the initial 5-week titration period or for >2 weeks while receiving venetoclax 400 mg once daily, reassess risk for tumor lysis syndrome to determine if a reduced dose is necessary when resuming therapy.1

Dosage Modification for Tumor Lysis Syndrome
Oral

If abnormalities in blood chemistry or symptoms consistent with tumor lysis syndrome occur, withhold next dose.1 If resolution occurs within 24–48 hours of the last dose, resume therapy at same dosage.1 However, if laboratory abnormalities require >48 hours to resolve or if clinical tumor lysis syndrome (clinical sequelae may include acute renal failure, cardiac arrhythmias, sudden death, seizures) occurs, resume therapy at a reduced dosage upon resolution.1 (See Tumor Lysis Syndrome under Cautions.)

Dosage Modification for Hematologic Toxicity
Oral

For first occurrence of grade 3 or 4 neutropenia associated with fever or infection, or grade 4 hematologic toxicity (except for lymphopenia), interrupt therapy and consider granulocyte colony-stimulating factor (G-CSF) if clinically indicated.1 Once toxicity resolves (i.e., improves to grade 1 or returns to baseline), resume at same dosage.1

For subsequent occurrences, interrupt therapy and administer G-CSF if clinically indicated.1 Once toxicity has resolved, resume at a reduced dosage.1

Dosage Modification for Nonhematologic Toxicity
Oral

For first occurrence of grade 3 or 4 nonhematologic toxicity, interrupt therapy until toxicity resolves (i.e., improves to grade 1 or returns to baseline); then resume at same dosage.1

For subsequent occurrences, interrupt therapy until toxicity resolves; then resume at a reduced dosage.1

Dosage Modification for Concomitant Therapy
Oral

If concomitant use of a potent CYP3A inhibitor is necessary in patients who have completed the initial dose titration and are receiving a steady daily dose of venetoclax, reduce dosage of venetoclax by at least 75%.1 When the potent CYP3A inhibitor is discontinued, resume previous dosage of venetoclax after 2–3 days.1

If concomitant use of a moderate inhibitor of CYP3A or inhibitor of P-glycoprotein (P-gp) is necessary, reduce dosage of venetoclax by at least 50%.1 When the moderate CYP3A or P-gp inhibitor is discontinued, resume previous dosage of venetoclax after 2–3 days.1 (See Interactions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (normal total bilirubin concentration with AST concentration exceeding ULN or total bilirubin concentration >1 to 1.5 times ULN): No dosage adjustment required.1 (See Hepatic Impairment under Cautions.)

Moderate hepatic impairment (total bilirubin concentration >1.5 to 3 times the ULN: No dosage adjustment required.1 Monitor for signs of toxicity during initial 5-week titration period.1

Severe hepatic impairment (total bilirubin >3 times ULN): Not studied.1

Renal Impairment

Mild (Clcr 60–89 mL/minute) or moderate (Clcr of 30–59 mL/minute) renal impairment: No dosage adjustment required.1

Severe renal impairment (Clcr <30 mL/minute) or dialysis: Not studied.1

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Venclexta

Contraindications

  • Concomitant use with potent CYP3A inhibitors at initiation of therapy and during dose-escalation period.1

Warnings/Precautions

Tumor Lysis Syndrome

Tumor lysis syndrome, sometimes fatal or resulting in acute renal failure requiring dialysis, reported.1 7 Risk generally greatest when drug is first initiated and during dose-escalation period; laboratory abnormalities requiring prompt medical treatment may occur as early as 6–8 hours following initial dose or after each dose increase.1

Risk is increased in patients with a high tumor burden (e.g., lymphocyte count ≥25,000/mm3).1 7 Renal impairment (Clcr <80 mL/minute) or concomitant use of certain drugs (moderate or potent CYP3A inhibitors or P-gp inhibitors) may further increase risk.1 (See Interactions.)

Assess patient's risk of tumor lysis syndrome (i.e., tumor burden, blood chemistries) and correct any abnormalities prior to initiating therapy and during dose-escalation period.1 (See General under Dosage and Administration.) Institute appropriate measures (e.g., prophylactic antihyperuricemic therapy and adequate hydration) to minimize risk; more intensive medical management (i.e., IV hydration, frequent monitoring, hospitalization) may be necessary as overall risk increases.1

If tumor lysis syndrome occurs, interrupt therapy until resolution; dosage reduction may be necessary once therapy resumed.1 (See Dosage Modification for Tumor Lysis Syndrome under Dosage and Administration.)

Neutropenia

Grade 3 or 4 neutropenia occurs commonly.1 7

Monitor CBC periodically during therapy.1 If hematologic toxicity occurs, temporary interruption of therapy or dosage reduction may be required.1 (See Dosage Modification for Hematologic Toxicity under Dosage and Administration.) Consider use of hematopoietic growth factors (e.g., G-CSF) and/or anti-infective therapy.1

Immunization

Safety and efficacy of immunization with live, attenuated vaccines during or following venetoclax therapy not established.1 Immune response to vaccines may be reduced.1

Avoid immunization with live, attenuated vaccines prior to, during, and following therapy until recovery of B-cell counts.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity (e.g., postimplantation loss, decreased fetal weight) demonstrated in animals; no evidence of teratogenicity.1

Avoid pregnancy during therapy.1 Perform pregnancy testing in women of childbearing potential prior to initiating therapy; such women should use effective contraception during therapy and for ≥30 days after drug is discontinued.1 (See Advice to Patients.) If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Impairment of Fertility

Based on animal studies, may impair male fertility.1 (See Advice to Patients.)

Specific Populations

Pregnancy

No available data in pregnant women; however, animal data suggest that drug may cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk or if drug has any effect on milk production or nursing infant.1 Discontinue nursing during therapy.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy relative to younger patients.1

Hepatic Impairment

Exposure may be increased since principally eliminated by liver.1 Clinical studies not specifically conducted; however, pharmacokinetic analysis suggests systemic exposure not altered by mild or moderate hepatic impairment.1 Not evaluated in patients with severe hepatic impairment.1

Renal Impairment

Clinical studies not specifically conducted; however, pharmacokinetic analysis suggests systemic exposure not altered by mild or moderate renal impairment.1 Not evaluated in patients with severe renal impairment or those requiring dialysis; not expected to be substantially removed by dialysis.1

Common Adverse Effects

Neutropenia,1 2 diarrhea,1 2 nausea,1 2 anemia,1 2 upper respiratory tract infection,1 2 thrombocytopenia,1 2 fatigue,1 2 hyperkalemia,1 pyrexia,1 2 headache,1 hyperphosphatemia,1 2 vomiting,1 2 constipation,1 2 nasopharyngitis,2 cough,1 hypokalemia,1 peripheral edema,1 back pain.1 2

Interactions for Venclexta

Principally metabolized by CYP3A4/5.1 5

Weak inhibitor of CYP isoenzymes 2C8 and 2C9 and uridine diphosphate-glucuronosyltransferase (UGT) 1A1; however, not expected to be clinically relevant.1

In vitro, neither an inhibitor nor inducer of CYP isoenzymes 1A2, 2B6, 2C19, 2D6, or 3A4 at clinically relevant concentrations.1 4 Does not inhibit UGT1A4, 1A6, 1A9, or 2B7 at clinically relevant concentrations.1

Substrate and inhibitor of P-gp and breast cancer resistance protein (BCRP); weak inhibitor of organic anion transport protein (OATP) 1B1.1 4 Not expected to inhibit OATP1B1, organic cation transporter (OCT) 1, OCT2, renal organic anion transporter (OAT) 1, OAT3, multidrug and toxic compound extrusion (MATE) 1, and MATE2K at clinically relevant concentrations.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased peak plasma concentrations and AUC of venetoclax.1 8 Concomitant use is contraindicated during initial dose-escalation period; if concomitant use is necessary once a steady daily dose of venetoclax has been reached, reduce venetoclax dosage by at least 75%.1 When the potent CYP3A inhibitor is discontinued, resume prior venetoclax dosage after 2–3 days.1 (See Specific Drugs and Foods under Interactions.)

Moderate CYP3A inhibitors: Possible increased peak plasma concentrations and AUC of venetoclax.1 Avoid concomitant use and consider an alternative agent with no or minimal enzyme inhibition potential.1 If concomitant use cannot be avoided, reduce venetoclax dosage by at least 50% and monitor closely for signs of toxicity.1 When the moderate CYP3A inhibitor is discontinued, resume prior venetoclax dosage after 2–3 days.1 (See Specific Drugs and Foods under Interactions.)

Moderate or potent CYP3A inducers: Possible decreased peak plasma concentrations and AUC of venetoclax.1 Avoid concomitant use and consider an alternative agent with no or minimal enzyme induction potential.1 (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Efflux Transport Systems

Inhibitors of P-gp: Possible increased peak plasma concentrations and AUC of venetoclax.1 Avoid concomitant use; consider an alternative agent with no or minimal P-gp inhibition potential.1 If concomitant use cannot be avoided, reduce venetoclax dosage by at least 50% and monitor closely for signs of toxicity.1 When the P-gp inhibitor is discontinued, resume prior venetoclax dosage after 2–3 days.1 (See Specific Drugs and Foods under Interactions.)

Substrates of Efflux Transport Systems

P-gp substrates: Possible pharmacokinetic interaction.1 Avoid concomitant use of venetoclax with P-gp substrates with a narrow therapeutic index.1 If such concomitant use cannot be avoided, administer substrate drug ≥6 hours prior to venetoclax.1

Drugs Affecting Gastric Acidity

Clinically important pharmacokinetic interactions not observed.1 8

Specific Drugs and Foods

Drug

Interaction

Comments

Amiodarone

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dose by 50%; when amiodarone is discontinued, resume prior venetoclax dose in 2–3 days1

Antacids

No substantial change in bioavailability of venetoclax1

Anticonvulsants (carbamazepine, phenytoin)

Possible decreased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use1

Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Ketoconazole: Increased venetoclax AUC (by 6.4-fold) and peak concentrations (by 2.3-fold)1

Itraconazole, ketoconazole, posaconazole, voriconazole: Contraindicated during initial venetoclax dose-escalation period1

Itraconazole, ketoconazole, posaconazole, voriconazole: If concomitant use is necessary once dose titration has been completed and patient is receiving a steady daily dose of venetoclax, reduce venetoclax dose by at least 75%; when the antifungal agent is discontinued, resume prior venetoclax dose in 2–3 days1

Fluconazole: Avoid concomitant use or reduce venetoclax dose by 50%; when fluconazole is discontinued, resume prior venetoclax dose in 2–3 days1

Antiretroviral agents, HIV protease inhibitors (e.g., indinavir, lopinavir, ritonavir)

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Contraindicated during initial venetoclax dose-escalation period1

If concomitant use is necessary once dose titration has been completed and patient is receiving a steady daily dose of venetoclax, reduce venetoclax dose by at least 75%; when the antiretroviral agent is discontinued, resume prior venetoclax dose in 2–3 days1

Antiretroviral agents, nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz, etravirine)

Possible decreased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use1

Azithromycin

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when azithromycin is discontinued, resume prior venetoclax dose in 2–3 days1

Bosentan

Possible decreased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use1

Calcium-channel blocking agents, nondihydropyridine (diltiazem, verapamil)

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dose by 50%; when the calcium-channel blocking agent is discontinued, resume prior venetoclax dose in 2–3 days1

Captopril

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when captopril is discontinued, resume prior venetoclax dose in 2–3 days1

Carvedilol

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when carvedilol is discontinued, resume prior venetoclax dose in 2–3 days1

Ciprofloxacin

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dose by 50%; when ciprofloxacin is discontinued, resume prior venetoclax dose in 2–3 days1

Conivaptan

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Contraindicated during initial venetoclax dose-escalation period1

If concomitant use is necessary once dose titration has been completed and patient is receiving a steady daily dose of venetoclax, reduce venetoclax dosage by at least 75%; when conivaptan is discontinued, resume prior venetoclax dose in 2–3 days1

Cyclosporine

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when cyclosporine is discontinued, resume prior venetoclax dose in 2–3 days1

Digoxin

Possible pharmacokinetic interaction due to P-gp inhibition by venetoclax1

Avoid concomitant use1

If concomitant use is unavoidable, administer digoxin ≥6 hours prior to venetoclax1

Dronedarone

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dose by 50%; when dronedarone is discontinued, resume prior venetoclax dose in 2–3 days1

Felodipine

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when felodipine is discontinued, resume prior venetoclax dose in 2–3 days1

Grapefruit or grapefruit juice

Possible increased venetoclax concentrations1

Avoid concomitant use1

Histamine H2-receptor antagonists

No substantial change in bioavailability of venetoclax1

Immunosuppressive agents (everolimus, sirolimus)

Possible pharmacokinetic interaction due to P-gp inhibition by venetoclax1

Avoid concomitant use1

If concomitant use is unavoidable, administer immunosuppressive agent ≥6 hours prior to venetoclax1

Macrolides (e.g., clarithromycin, erythromycin)

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Clarithromycin: Contraindicated during initial venetoclax dose-escalation period 1

Clarithromycin: If concomitant use is necessary once dose titration has been completed and patient is receiving a steady daily dose of venetoclax, reduce venetoclax dose by at least 75%; when clarithromycin is discontinued, resume prior venetoclax dose in 2–3 days1

Erythromycin: Avoid concomitant use or reduce venetoclax dose by 50%; when erythromycin is discontinued, resume prior venetoclax dose in 2–3 days1

Modafinil

Possible decreased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use1

Nafcillin

Possible decreased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use1

Proton-pump inhibitors

No substantial change in bioavailability of venetoclax1

Quercetin

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when quercetin is discontinued, resume prior venetoclax dose in 2–3 days1

Quinidine

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when quinidine is discontinued, resume prior venetoclax dose in 2–3 days1

Ranolazine

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when ranolazine is discontinued, resume prior venetoclax dose in 2–3 days1

Rifampin

Decreased venetoclax AUC (by 71%) and peak concentrations (by 42%) with repeat dosing of rifampin1 5

Increased venetoclax AUC (by 78%) and peak concentrations (by 106%) with single-dose administration of rifampin1 5

Avoid concomitant use1

Seville oranges

Possible increased venetoclax concentrations1

Avoid concomitant use1

Starfruit

Possible increased venetoclax concentrations1

Avoid concomitant use1

St. John’s wort (Hypericum perforatum)

Possible decreased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use1

Ticagrelor

Possible increased peak plasma concentrations and systemic exposure of venetoclax1

Avoid concomitant use or reduce venetoclax dosage by 50%; when ticagrelor is discontinued, resume prior venetoclax dose in 2–3 days1

Vaccines, live

Immune response to vaccines may be reduced1

Avoid live vaccines1 (see Immunization under Cautions)

Warfarin

Increased venetoclax AUC and peak concentrations by 18–28%1

Closely monitor INR1

Venclexta Pharmacokinetics

Absorption

Bioavailability

Exhibits linear pharmacokinetics over the dose range of 150–800 mg.1 7

Following oral administration under fed conditions, peak plasma concentrations are attained in 5–8 hours.1 7

Food

Oral administration with a low-fat or high-fat meal increases AUC by 3.4- and 5.2-fold, respectively.1 6

Special Populations

In patients with mild or moderate hepatic impairment, systemic exposure similar to that in patients with normal hepatic function.1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

In patients with mild or moderate renal impairment, systemic exposure similar to that in patients with normal renal function.1 Pharmacokinetics not studied in patients with severe renal impairment or those requiring dialysis.1

Distribution

Extent

Not known whether distributed into milk.1

Plasma Protein Binding

>99%.1

Elimination

Metabolism

Metabolized principally by CYP3A4/5 to the major metabolite, M27.1

Elimination Route

Eliminated in feces (99.9%) and urine (<0.1%) within 9 days.1

Half-life

Mean terminal half-life approximately 26 hours.1 8

Special Populations

Age (range: 25–88 years), gender, race, and body weight do not substantially affect clearance of venetoclax.1 8

Stability

Storage

Oral

Tablets

≤30°C.1

Store tablets in original package during initial 4 weeks of therapy.1

Actions

  • Potent and selective inhibitor of BCL-2.1 2 7 9 10

  • Binds to BCL-2, displaces pro-apoptotic proteins (e.g., BIM), induces mitochondrial outer membrane permeabilization, and activates caspases resulting in restoration of intrinsic apoptotic pathway.1 9 10

  • Demonstrated cytotoxic activity in tumor cells overexpressing BCL-2.1

Advice to Patients

  • Importance of taking venetoclax exactly as prescribed with food and water.1 Avoid grapefruit products, Seville oranges, and starfruit while taking the drug.1

  • Importance of storing venetoclax tablets in the original package during initial 4 weeks of therapy.1

  • Importance of advising patients to swallow venetoclax tablets whole and to not chew, crush, or break the tablets.1

  • If a dose is missed, importance of advising patients to take it as soon as they remember and resume the next dose at the regularly scheduled time unless the dose was missed by >8 hours, in which case they should not take the missed dose.1 If a dose is vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.1

  • Risk of tumor lysis syndrome.1 Importance of maintaining scheduled appointments for blood work and other laboratory tests.1 Importance of immediately reporting any signs or symptoms of tumor lysis syndrome (e.g., fever, chills, nausea, vomiting, confusion, shortness of breath, seizure, arrhythmia, dark or cloudy urine, fatigue, muscle pain, joint discomfort).1 Importance of advising patients to maintain adequate hydration during venetoclax therapy.1 The recommended volume is 6–8 glasses (approximately 56 ounces) a day.1 Patients should start drinking water 2 days before initiating venetoclax, on the day of the first dose, and each time the dose is increased.1

  • Risk of neutropenia.1 Importance of monitoring CBC periodically during venetoclax therapy.1 Importance of immediately reporting any signs or symptoms of infection (e.g., fever).1

  • Importance of avoiding use of live vaccines prior to, during, and following venetoclax therapy until B-cell count recovery.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for ≥30 days after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Risk of male infertility.1 Importance of advising men of reproductive potential to consider sperm banking.1

  • Importance of advising women to avoid breast-feeding while receiving venetoclax.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Venetoclax

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

10 mg

Venclexta

Genentech

50 mg

Venclexta

Genentech

100 mg

Venclexta

Genentech

Titration Pack

14 Tablets, Venetoclax 10 mg (Venclexta)

7 Tablets, Venetoclax 50 mg (Venclexta)

7 Tablets, Venetoclax 100 mg (Venclexta)

14 Tablets, Venetoclax 100 mg (Venclexta)

Venclexta Starting Pack

Genentech

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: October 26, 2016
Last reviewed: October 26, 2016
Date modified: November 09, 2016

References

1. Genentech. Venclexta (venetoclax) tablets prescribing information. South San Francisco, CA; 2016 Apr.

2. Stilgenbauer S, Eichhorst B, Schetelig J et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016; 17:768-78. [PubMed 27178240]

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2016 Jun 21.

4. Weiss J, Gajek T, Köhler BC et al. Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions. Pharmaceutics. 2016; 8:. [PubMed 26927160]

5. Agarwal SK, Hu B, Chien D et al. Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a Bcl-2 Inhibitor: Results of a Single- and Multiple-dose Study. J Clin Pharmacol. 2016; :. [PubMed 26953185]

6. Salem AH, Agarwal S, Dunbar M et al. Effect of Low and High Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First-in-Class Bcl-2 Inhibitor. J Clin Pharmacol. 2016; :. [PubMed 27029823]

7. Roberts AW, Davids MS, Pagel JM et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016; 374:311-22. [PubMed 26639348]

8. Jones AK, Freise KJ, Agarwal SK et al. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis. AAPS J. 2016; :. [PubMed 27233802]

9. Anderson MA, Deng J, Seymour JF et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53 independent mechanism. Blood. 2016; :. [PubMed 27069256]

10. Ng SY, Davids MS. Selective Bcl-2 inhibition to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma. Clin Adv Hematol Oncol. 2014; 12:224-9. [PubMed 25003352]

11. Jones J, Mato A, Coutre S et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after refractory to ibrutinib or idelalisib therapy. Oral presentation at 57th Annual Meeting of the American Society of Hematology. Orlando, FL: 2015 Dec 7.

12. US Food and Drug Administration. Medical review(s)/statistical review(s): NDA 208573Orig1S000. From FDA website.

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