venetoclax

ven-ET-oh-klax

Therapeutic Classification: antineoplastics

Pharmacologic Classification: bcl 2 inhibitors

REMS

Chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) (as monotherapy or in combination with obinutuzumab or rituximab).
Newly diagnosed acute myeloid leukemia (AML) in patients who are ≥75 yr old or who have comorbidities that prevent the use of intensive induction chemotherapy (in combination with azacitidine or decitabine or low-dose cytarabine).

Inhibits BCL-2 which is overexpressed on CLL, SLL, and AML cells, thereby inducing apoptosis.

Therapeutic effects:

Reduced disease progression.

Absorption: Well absorbed with food following oral administration; bioavailability ↑ by high-fat foods.

Distribution: Extensively distributed to tissues.

Protein Binding: 99%.

Metabolism/Excretion: Primarily metabolized by CYP3A4/5. 99% excreted in feces (21% as unchanged drug).

Half-Life: 26 hr.

(blood levels)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	5–8 hr	unknown

Contraindicated in:

Concurrent use with strong CYP3A inhibitors during initiation and ramp-up phases;
Concurrent use with moderate CYP3A inhibitors or P-gp inhibitors;
Concurrent use with strong or moderate CYP3A inducers;
OB: Pregnancy (may cause fetal harm);
Lactation: Lactation.

Use Cautiously in:

High tumor burden (↑ risk of tumor lysis syndrome);
Renal impairment (CCr <80 mL/min) (↑ risk of tumor lysis syndrome);
Splenomegaly (↑ risk of tumor lysis syndrome);
Severe hepatic impairment (↓ dose);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: peripheral edema

F and E: hyperkalemia, hyperphosphatemia, hypokalemia, hyperuricemia, hypocalcemia

GI: constipation, diarrhea, nausea, vomiting

GU: ↓fertility (males)

Hemat: anemia, neutropenia, thrombocytopenia

MS: back pain

Neuro: headache

Resp: cough

Misc: fatigue, fever, INFECTION, TUMOR LYSIS SYNDROME

Drug-drug:

Strong CYP3A inhibitors, including itraconazole, conivaptan, clarithromycin, lopinavir, ritonavir, posaconazole, and voriconazole may ↑ levels; concurrent use during initiation and ramp-up phase in CLL/SLL contraindicated; ↓ venetoclax dose during initiation and ramp-up phase in AML; ↓ venetoclax dose after ramp-up phase for CLL, SLL, and AML if concurrent use necessary.
Moderate CYP3A4 inhibitors, including erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, or verapamil or P-gp inhibitors, including amiodarone, azithromycin, captopril, carvedilol, cyclosporine, felodipine, quinidine, ranolazine, or ticagrelor may ↑ levels; avoid concurrent use; ↓ venetoclax dose if concurrent use necessary.
Strong CYP3A4 inducers, including carbamazepine, phenytoin, or rifampin or moderate CYP3A inducers, including bosentan, efavirenz, etravirine, modafinil, or nafcillin may ↓ levels; avoid concurrent use.
May ↑ levels of P-gp substrates with a narrow therapeutic index, including digoxin, sirolimus, and everolimus; if concurrent therapy necessary, give P-gp substrate ≥6 hr before venetoclax.
May ↑ levels of warfarin.
May ↓ antibody response to live-virus vaccine and ↑ risk of adverse reactions; do not administer concurrently.

Drug-Natural Products:

St. John's wort may ↓ levels; avoid concurrent use.

Grapefruit products, Seville oranges, and starfruit may ↑ levels; avoid concurrent use.

Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

PO (Adults ): Monotherapy: Start with the following 5–wk venetoclax ramp-up phase: 20 mg once daily during Wk 1, then 50 mg once daily during Wk 2, then 100 mg once daily during Wk 3, then 200 mg once daily during Wk 4, then 400 mg once daily during Wk 5. After completion of ramp-up phase, continue venetoclax therapy at 400 mg once daily until disease progression or unacceptable toxicity. In combination with rituximab: Start with the following 5–wk venetoclax ramp-up phase: 20 mg once daily during Wk 1, then 50 mg once daily during Wk 2, then 100 mg once daily during Wk 3, then 200 mg once daily during Wk 4, then 400 mg once daily during Wk 5. After completion of ramp-up phase, start rituximab which will be administered on Day 1 of each 28–day cycle for a total of 6 cycles. Continue venetoclax therapy at 400 mg once daily starting on Day 1 of Cycle 1 and continue for 24 mo (from Day 1 of Cycle 1). In combination with obinutuzumab: Start with obinutuzumab on Days 1, 2, 8, and 15 of Cycle 1 and then on Day 1 of each subsequent 28–day cycle for a total of 6 cycles. On Day 22 of Cycle 1, start 5–wk venetoclax ramp-up phase: 20 mg once daily during Wk 1, then 50 mg once daily during Wk 2, then 100 mg once daily during Wk 3, then 200 mg once daily during Wk 4, then 400 mg once daily during Wk 5. After completion of ramp-up phase on Day 28 of Cycle 2, continue venetoclax therapy at 400 mg once daily from Day 1 of Cycle 3 until Day 28 of Cycle 12. Concurrent use of strong CYP3A inhibitors (including posaconazole) (during ramp–up phase): Contraindicated; Concurrent use of posaconazole (after ramp–up phase): ↓venetoclax dose to 70 mg once daily. Concurrent use of strong CYP3A inhibitors other than posaconazole (after ramp–up phase): ↓venetoclax dose to 100 mg once daily. Concurrent use of moderate CYP3A inhibitors or P-gp inhibitors (during or after ramp–up phase): ↓venetoclax dose by≥50%.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment: ↓dose by 50%.

Acute Myeloid Leukemia

PO (Adults ): In combination with azacitidine or decitabine: Start with the following venetoclax ramp-up phase: 100 mg on Day 1, then 200 mg on Day 2, then 400 mg on Day 3, then 400 mg on Day 4. After completion of ramp-up phase, continue venetoclax therapy at 400 mg once daily until disease progression or unacceptable toxicity. Start azacitidine or decitabine on Day 1. In combination with low-dose cytarabine: Start with the following venetoclax ramp-up phase: 100 mg on Day 1, then 200 mg on Day 2, then 400 mg on Day 3, then 600 mg on Day 4. After completion of ramp-up phase, continue venetoclax therapy at 600 mg once daily until disease progression or unacceptable toxicity. Start low-dose cytarabine on Day 1. Concurrent use of posaconazole: ↓venetoclax dose during ramp-up phase to 10 mg on Day 1, then 20 mg on Day 2, then 50 mg on Day 3, then 70 mg on Day 4. After completion of ramp-up phase, ↓ venetoclax dose to 70 mg once daily. Concurrent use of strong CYP3A inhibitors other than posaconazole: ↓venetoclax dose during ramp-up phase to 10 mg on Day 1, then 20 mg on Day 2, then 50 mg on Day 3, then 100 mg on Day 4. After completion of ramp-up phase, ↓ venetoclax dose to 100 mg once daily. Concurrent use of moderate CYP3A inhibitors or P-gp inhibitors: ↓venetoclax dose by≥50% during or after completion of ramp-up phase.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment: ↓dose by 50%.

Tablets: 10 mg; 50 mg; 100 mg

Assess for risk of tumor lysis syndrome and provide prophylactic hydration and anti-hyperuricemic agents prior to 1st dose to reduce tumor lysis syndrome. Prophylaxis for patients with a low tumor burden (All lymph node (LN) <5 cm AND absolute lymphocyte count (ALC) <25 x 10⁹/L) includes allopurinol with oral hydration of 1.5–2 L. Monitor blood chemistries (potassium, uric acid, phosphorous, calcium, serum creatinine) on an outpatient basis at pre-dose, 6–8 hrs, 24 hrs at 1st dose of 20 mg and 50 mg and Pre-dose at subsequent ramp-up doses. Prophylaxis for patients with a medium tumor burden (Any LN 5 cm-<10 cm OR ALC ≥25 x 10⁹/L) includes allopurinol and oral hydration of 1.5–2 L and consider additional IV hydration. Monitor blood chemistries on an outpatient basis at pre-dose, 6–8 hrs, 24 hrs at 1st dose of 20 mg and 50 mg and Pre-dose at subsequent ramp-up doses. Consider hospitalization for patients with creatinine clearance <80 mL/min at 1st dose of 20 mg and 50 mg. Prophylaxis for patients with a high tumor burden (Any LN ≥10 cm OR ALC ≥25 x 10⁹/L AND any LN ≥5 cm) includes allopurinol; consider rasburicase if baseline uric acid ↑, and oral hydration of 1.5–2 L and IV 150–200 mL/hr as tolerated. Monitor blood chemistries in hospital at 1st dose of 20 mg and 50 mg, pre-dose, 4, 8, 12, and 24 hrs; outpatient at subsequent ramp-up doses, pre-dose, 6–8 hrs, and 24 hrs. Administer IV hydration for patients who cannot tolerate oral hydration. Start allopurinol or xanthine oxidase inhibitor 2–3 days prior to starting venetoclax.
Monitor for signs and symptoms of infection (fever, chills, dyspnea). Treat infections promptly.
Monitor for non-hematologic toxicities (pneumonia, fever, diarrhea, nausea, upper respiratory infection, fatigue) during therapy. For 1st occurrence of Grade 3 or 4 non-hematologic toxicities, interrupt venetoclax. Once toxicity resolved to Grade 1 or baseline, may resume at same dose. For 2nd and subsequent occurrences, interrupt venetoclax. After resolution, resume at decreased dose: if 400 mg resume at 300 mg, if 300 mg resume at 200 mg, if 200 mg resume at 100 mg, if 100 mg resume at 50 mg, if 50 mg resume at 20 mg, if 20 mg resume at 10 mg.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.Assess blood chemistry (serum potassium, uric acid, phosphorous, calcium, creatinine) and correct pre-existing abnormalities prior to starting therapy. For blood chemistry changes or symptoms of tumor lysis syndrome, withhold next day's dose. If resolved within 24–48 hrs of last dose, resume at same dose. If >48 hrs to resolve, resume at reduced dose. If clinical tumor lysis syndrome (renal failure, cardiac arrhythmias, sudden death, seizures) occurs, resume at reduced dose after resolution.
- Monitor CBC periodically during therapy. May cause neutropenia, anemia, thrombocytopenia, and febrile neutropenia. If 1st occurrence of Grade 3 or 4 neutropenia with infection or fever; or Grade 4 hematologic toxicities (except lymphoma), interrupt venetoclax. May administer granulocyte-colony stimulating factor (G-CSF) to reduce risks of infection. Once toxicity resolved to Grade 1 or baseline, may resume venetoclax at same dose. For 2nd and subsequent occurrences, interrupt venetoclax. Consider using G-CSF as clinically indicated. Resume therapy at reduced dose. If patient required dose reductions to <100 mg for >2 wk, consider discontinuing venetoclax.

PO: Administer with a meal and water at same time each day. DNC: Swallow tablets whole; do not break, crush, or chew.

Instruct patient to take venetoclax as directed; do not change dose or stop taking venetoclax without consulting health care professional. Keep in original packaging for first 4 wk of therapy; do not transfer to another container. Take missed doses as soon as possible within 8 hrs of usual dose time. If missed by >8 hrs, omit and resume next day. If patient vomits do not replace dose.
Advise patient to avoid grapefruit products, Seville oranges, or starfruit during therapy.
Advise patient to avoid live vaccines prior to, during, or after treatment until B-cell recovery occurs.
Advise patient to notify health care professional immediately if signs and symptoms of neutropenia (fever, signs of infection) or tumor lysis syndrome (fever, chills, nausea, vomiting, confusion, shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, unusual tiredness, muscle pain, joint discomfort) occur. Advise patient to hydrate with 6–8 glasses of water/day starting 2 days before and on day of 1st dose and every dose increase to reduce risk of tumor lysis syndrome.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Emphasize importance of regular blood work and laboratory tests.
Rep: May cause fetal harm. Use effective contraception during and for at least 30 days after last dose and avoid breastfeeding during and for 1 wk after last dose of therapy. May impair male fertility; consider sperm banking for males of reproductive potential.

Reduced disease progression.

Venclexta

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