venetoclax (Rx)

Brand and Other Names:Venclexta
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 10mg
  • 50mg
  • 100mg

Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Indicated for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least 1 prior therapy

Monotherapy

  • 20 mg PO qDay for 7 days initially, followed by a weekly ramp-up dosing schedule over 5 weeks to the recommended daily dose of 400 mg
  • Dose ramp-up phase
    • Administer dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg
    • Week 1: 20 mg PO qDay
    • Week 2: 50 mg PO qDay
    • Week 3: 100 mg PO qDay
    • Week 4: 200 mg PO qDay
    • Week 5 and beyond: 400 mg PO qDay
    • Continue until disease progression or unacceptable toxicity

Combination with rituximab

  • In combination with rituximab, administer rituximab after the 5-week ramp-up schedule with venetoclax
  • Administer rituximab 375 mg/m² IV for Cycle 1 on Day 1, followed by 500 mg/m² IV on Day 1 for Cycles 2-6
  • Continue venetoclax 400 mg PO qDay for 24 months from Cycle 1 Day 1 of rituximab

Acute Myeloid Leukemia

In combination with azacitidine or decitabine or low-dose cytarabine for the treatment in adults (≥75 years) who are newly-diagnosed acute myeloid leukemia (AML) or who have comorbidities that preclude use of intensive induction chemotherapy

Venetoclax dosing depends on the combination agent

Dose ramp-up phase

  • Day 1: 100 mg PO qDay
  • Day 2: 200 mg PO qDay
  • Day 3: 400 mg PO qDay
  • Day 4 and beyond (in combination with decitabine or azacitidine): 400 mg PO qDay
  • Day 4 and beyond (in combination with low-dose cytarabine): 600 mg PO qDay
  • In combination with decitabine, azacitidine, or low-dose cytarabine: Continue until disease progression or unacceptable toxicity

Dosage Modifications

For patients who have had a dosing interruption >1 week during the first 5 weeks of ramp-up phase or >2 weeks after completing the ramp-up phase, reassess for risk of tumor lysis syndrome (TLS) to determine if reinitiation with a reduced dose is necessary (eg, all or some levels of the dose ramp-up schedule)

Consider discontinuing treatment for patients who require dose reductions to <100 mg for >2 weeks

Dose reduction schedule

  • Dose at interruption 400 mg: Restart at 300 mg
  • Dose at interruption 300 mg: Restart at 200 mg
  • Dose at interruption 200 mg: Restart at 100 mg
  • Dose at interruption 100 mg: Restart at 50 mg
  • Dose at interruption 50 mg: Restart at 20 mg
  • Dose at interruption 20 mg: Restart at 10 mg
  • During the ramp-up phase, continue reduced dose for 1 week before increasing the dose

Tumor lysis syndrome

  • Modify for any occurrence of blood chemistry changes or symptoms suggestive of TLS
  • Withhold the next day’s dose; if resolved within 24-48 hr of last dose, resume at the same dose
  • For any blood chemistry changes requiring >48 hr to resolve, resume at a reduced dose
  • For any events of clinical TLS, resume at a reduced dose following resolution

Grade 3 or 4 nonhematologic toxicities

  • First occurrence: Interrupt dose; once resolved to Grade ≤1, resume at same dose; no dose modification is required
  • Second and subsequent occurrences: Interrupt dose; follow dose reduction schedule when resuming treatment after resolution; a larger dose reduction may occur at discretion of physician

Hematologic toxicities (CLL/SLL)

  • Grade 3 or 4 neutropenia with infection or fever, or Grade 4 hematologic toxicities (except lymphopenia)
  • First occurrence: Interrupt dose; reduce infection risks with neutropenia by administering G-CSF with venetoclax if clinically indicated; once toxicity resolves to Grade ≤1, resume at the same dose
  • Second and subsequent occurrences: Interrupt dose; consider using G-CSF as clinically indicated; follow dose reduction schedule when resuming treatment after resolution; a larger dose reduction may occur at discretion of physician

Hematologic toxicities (AML)

  • Grade 4 neutropenia with or without fever or infection; or Grade 4 thrombocytopenia
  • Occurrence prior to achieving remission: Transfuse blood products, administer prophylactic and treatment anti-infectives as clinically indicated
  • First occurrence after remission (last ≥7 days): Delay subsequent treatment cycle of venetoclax and azacitidine, decitabine, or low-dose cytarabine; monitor blood counts; once resolved to Grade 1 or 2, resume all therapy at same dose
  • Subsequent occurrence after remission (last ≥7 days): Delay subsequent treatment cycle of venetoclax and azacitidine, decitabine, or low-dose cytarabine; monitor blood counts; once resolved to Grade 1 or 2, resume all therapy at same dose and reduce duration by 7 days for each subsequent cycle

Coadministration with strong CYP3A4 inhibitors

  • CLL/SLL
    • Dose ramp-up phase: Contraindicated
    • After ramp-up phase, consider alternative medications or reduce dose to 70 mg (coadministered with posaconazole) and 100 mg (coadministered with other strong CYP3A4 inhibitors)
  • AML
    • Day 1: Reduce to 10 mg
    • Day 2: Reduce to 20 mg Day 3: Reduce to 50 mg
    • Day 4: Reduce to 70 mg (coadministered with posaconazole) OR 100 mg (coadministered with other strong CYP3A4 inhibitors
    • Steady daily dose (after ramp-up phase): Reduce dose to 70 mg (coadministered with posaconazole) and 100 mg (coadministered with other strong CYP3A4 inhibitors)
    • Resume venetoclax dose used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2-3 days after discontinuation of inhibitor

Coadministration with moderate CYP3A inhibitor or P-gp inhibitor

  • Reduce venetoclax dose by at least 50%
  • Resume venetoclax dose used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2-3 days after discontinuation of the inhibitor

Renal impairment

  • Mild or moderate (CrCl ≥30 mL/min): No dosage adjustment necessary
  • Severe (CrCl <30 mL/min) or patients on dialysis: Recommended dose has not been determined

Hepatic impairment

  • Mild or moderate: No dosage adjustment; closely monitor patients for signs of toxicity during initiation and ramp-up phase

Dosing Considerations

Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur

Acute myeloid leukemia

  • Approved under accelerated approval based on response rates
  • Continued approval for indication may contingent upon verification and description of clinical benefit in confirmatory trials

TLS risk

  • Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and antihyperuricemics prior to first dose to reduce risk of TLS
  • Perform tumor burden assessments, including radiographic evaluation (eg, CT scan)
  • Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct preexisting abnormalities prior to initiation; monitor blood chemistries for TLS
  • AML: All patients should have WBC<25 x 10^9/L prior to initiation

TLS prophylaxis (CLL/SLL)

  • Low tumor burden (all lymph nodes (LNs) <5 cm AND absolute lymphocyte count (ALC) <25 x10^9/L)
    • Hydration: Oral (1.5-2 L)
    • Give allopurinol or xanthine oxidase inhibitor (2-3 days prior to initiation)
    • Administer IV hydration for patients unable to tolerate oral hydration
    • Outpatient monitoring (20-mg or 50-mg dose): Blood chemistry predose, at 6-8 hr, and 24 hr after first dose and predose for subsequent ramp-up doses
  • Medium tumor burden (any LN 5 to <10 cm OR ALC ≥25 x10^9/L)
    • Hydration: Oral (1.5-2 L, also consider additional IV hydration)
    • Give allopurinol or xanthine oxidase inhibitor (2-3 days prior to initiation)
    • Administer IV hydration for patients unable to tolerate oral hydration
    • Outpatient monitoring (20-mg or 50-mg dose): Blood chemistry predose, at 6-8 hr, and 24 hr after first dose and predose for subsequent ramp-up doses; consider hospitalization for patients with CrCl <80 mL/min at first dose
  • High tumor burden (any LN ≥10 cm OR ALC ≥25 x10^9/L AND any LN ≥5 cm)
    • Hydration: Oral (1.5-2 L) and IV (150-200 mL/hr as tolerated)
    • Give allopurinol 2-3 days before initiating venetoclax; consider rasburicase if baseline uric acid is elevated
    • Inpatient monitoring (20-mg or 50-mg dose): Blood chemistry predose, 4, 8, 12, and 24 hr
    • Outpatient monitoring (subsequent ramp-up doses): Blood chemistry at predose, at 6-8 hr, and 24 hr after dose

Orphan Designations

Multiple myeloma

Mantle cell lymphoma

Sponsor

  • AbbVie Inc; 1 Waukegan Road, Dept PA77, Bldg. AP30; North Chicago, Illinois 60044

Safety and efficacy not established

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Interactions

Interaction Checker

and venetoclax

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     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            All grades of severity listed unless otherwise indicated

            >10% (Combination with rituximab)

            Leukopenia (89%)

            Lymphopenia (87%)

            Neutropenia (65-86%)

            Neutropenia, Grade 3 or 4 (62-64%)

            Hypocalcemia (62%)

            Hypophosphatemia (57%)

            Lymphopenia, Grade 3 or 4 (56%)

            Leukopenia, Grade 3 or 4 (46%)

            Diarrhea (43%)

            Increased AST/SGOT (46%)

            Diarrhea (40%)

            Upper respiratory tract infection (39%)

            Hyperuricemia (36%)

            Increased alkaline phosphatase (35%)

            Hyperbilirubinemia (33%)

            Hyponatremia (30%)

            Hypokalemia (29%)

            Hyperkalemia (24%)

            Hypernatremia (24%)

            Nausea (21%)

            Musculoskeletal pain (19%)

            Lower respiratory tract infection (18%)

            Anemia (16%)

            Thrombocytopenia (15%)

            Constipation (14%)

            Hypophosphatemia, Grade 3 or 4 (14%)

            Abdominal pain (13%)

            Rash (13%)

            Headache (11%)

            Insomnia (11%)

            >10% (Monotherapy)

            Neutropenia (50%)

            Neutropenia, Grade 3 or 4 (45%)

            Nausea (42%)

            Upper respiratory tract infection (36%)

            Anemia (33%)

            Fatigue (32%)

            Thrombocytopenia (29%)

            Edema (22%)

            Thrombocytopenia, Grade 3 or 4 (20%)

            Anemia, Grade 3 or 4 (18%)

            Abdominal pain (18%)

            Pyrexia (18%)

            Vomiting (16%)

            Constipation (16%)

            Mucositis (13%)

            Lymphopenia (11%)

            1-10% (Combination with rituximab)

            Mucositis (10%)

            Pneumonia (10%)

            Vomiting (8%)

            Lymphopenia, Grade 3 or 4 (7%)

            Hyponatremia, Grade 3 or 4 (6%)

            Hypokalemia, Grade 3 or 4 (6%)

            Hypocalcemia, Grade 3 or 4 (5%)

            Febrile neutropenia (4%)

            Hyperbilirubinemia, Grade 3 or 4 (4%)

            Diarrhea, Grade 3 or 4 (3%)

            Tumor lysis syndrome, Grade 3 or 4 (3%)

            Hyperkalemia, Grade 3 or 4 (3%)

            Upper respiratory tract infection, Grade 3 or 4 (2%)

            Lower respiratory tract infection, Grade 3 or 4 (2%)

            Increased AST/SGOT (2%)

            Hypernatremia, Grade 3 or 4 (1%)

            Musculoskeletal pain, Grade 3 or 4 (1%)

            Increased alkaline phosphatase, Grade 3 or 4 (1%)

            1-10% (Monotherapy)

            Febrile neutropenia (6%)

            Fatigue, Grade 3 or 4 (4%)

            Abdominal pain, Grade 3 or 4 (3%)

            Diarrhea, Grade 3 or 4 (3%)

            Edema, Grade 3 or 4 (2%)

            Nausea, Grade 3 or 4 (1%)

            Vomiting, Grade 3 or 4 (1%)

            Upper respiratory tract infection, Grade 3 or 4 (1%)

            <1%

            Monotherapy

            • Constipation, Grade 3 or 4
            • Mucositis, Grade 3 or 4
            • Pyrexia, Grade 3 or 4
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            Warnings

            Contraindications

            Strong CYP3A inhibitors at initiation and during ramp-up phase

            Cautions

            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 venetoclax

            Neutropenia frequently reported; monitor complete blood counts throughout the treatment period

            Do not administer live attenuated vaccines prior to, during, or after treatment until B-cell recovery occurs; safety and efficacy of immunization with live attenuated vaccines during or following therapy have not been studied; advise patients that vaccinations may be less effective

            Based on its mechanism of action and findings in animals, may cause embryofetal harm when administered to a pregnant woman

            Drug interaction overview

            • Venetoclax is a CYP3A substrate
            • Coadministration with CYP3A inhibitors: Contraindicated during ramp-up phase; reduce dose of venetoclax while on steady daily dose
            • Coadministration with moderate CYP3A inhibitor and P-gp inhibitors: Reduce dose of venetoclax
            • If inhibitor discontinued, resume venetoclax dose used prior to initiating the CYP3A or P-gp inhibitor
            • Concomitant use with a strong CYP3A inducer decreases venetoclax peak plasma concentration and AUCinf which may decrease venetoclax efficacy; avoid concomitant use with strong or moderate CYP3A inducers
            • Venetoclax effect on other drugs
              • Venetoclax has inhibition potential on P-gp substrates at therapeutic dose levels in the gut; therefore, avoid coadministration with narrow therapeutic index P-gp substrates
              • Administration of a single dose of venetoclax with warfarin resulted in an 18-28% increase in Cmax and AUC of R-warfarin and S-warfarin; monitor INR closely if coadministered
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            Pregnancy

            Pregnancy

            There are no available human data on use in pregnant women; based on its mechanism of action and findings in animals, may cause embryofetal harm when administered to a pregnant woman

            Females of reproductive potential should undergo pregnancy testing before initiation

            Animal studies

            • 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

            Fertility and contraception

            • Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after the last dose
            • Male fertility may be compromised by treatment

            Lactation

            Unknown if distributed in human breast milk; advise nursing women to discontinue breastfeeding during treatment

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein

            Overexpression of Bcl-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutic agents

            Venetoclax helps restore the process of apoptosis by binding directly to the Bcl-2 protein, displacing proapoptotic proteins like BIM (a novel member of the Bcl-2 family), triggering mitochondrial outer membrane permeabilization, and activating caspases

            Absorption

            Peak plasma time: 5-8 hr

            Peak plasma concentration: 2.1 mcg/mL (400 mcg//day)

            AUC: 32.8 mcg·hr/mL (400 mcg//day)

            Distribution

            Protein bound: >99.9%

            Vd: 256-321 L

            Metabolism

            Metabolized by CYP3A4/5

            M27 was identified as a major metabolite in plasma with an inhibitory activity against Bcl-2 that is at least 58-fold lower than venetoclax in vitro

            Elimination

            Half-life: 26 hr

            Excretion: >99.9% in feces; <0.1% in urine

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            Administration

            Oral Administration

            Administer 1 time a day with a meal and water at about the same time each day

            Swallow whole; do not chew, crush, or break the tablets

            Missed dose

            • If dose is missed within 8 hr of the time it is usually taken, take as soon as possible
            • If a patient misses a dose by >8 hr, skip dose and resume the usual dosing schedule the next day
            • If the patient vomits following dosing, do not take an extra dose; the next prescribed dose should be taken at the usual time

            Storage

            Tablets: Store at ≥86°F (30°C); keep tablets in the original package during the first 4 weeks of treatment; do not transfer the tablets to a different container

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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