Dosing and uses of Venclexta (venetoclax)
Adult dosage forms and strengths
tablet
- 10mg
- 50mg
- 100mg
Chronic Lymphocytic Leukemia (CLL)
Indicated for patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least 1 prior therapy
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 daily dose until disease progression or unacceptable toxicity
- See Dosing Considerations and Dosage modifications for tumor lysis syndrome (TLS) prophylaxis regimens
Dosage modifications
Dose reduction schedule
- Dose at interruption is 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 the 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
Nonhematologic toxicities (grades 3 or 4)
- First occurrence: Interrupt dose; once the toxicity has resolved to grade 1 or baseline level, may resume at the same dose; no dose modification is required
- Second and subsequent occurrences: Interrupt dose; once the toxicity has resolved to grade 1 or baseline level, decrease dose according instructions listed above; a larger dose reduction may occur at the discretion of the physician
Hematologic toxicities
- The following applies to grades 3 or 4 neutropenia with infection or fever, or grade 4 hematologic toxicities (except lymphopenia)
- First occurrence: Interrupt dose; to reduce the infection risks with neutropenia, G-CSF may be administered with venetoclax if clinically indicated; once the toxicity has resolved to grade 1 or baseline level, may resume at the same dose
- Second and subsequent occurrences: Interrupt dose; consider using G-CSF as clinically indicated; follow dose reduction listed above when resuming after resolution; a larger dose reduction may occur at the discretion of the physician
Coadministration with CYP3A and/or P-gp inhibitors
- Strong CYP3A inhibitor
- Contraindicated during initiation and ramp-up phase
- At steady daily dose (ie, after ramp-up phase): Avoid strong inhibitor or reduce venetoclax dose by at least 75%
- Moderate CYP3A inhibitor or P-gp inhibitor
- Avoid strong inhibitor or reduce venetoclax dose by at least 50%
Dosing Considerations
Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur
TLS risk
- Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and antihyperuricemics to patients prior to first dose to reduce risk of TLS
- Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5week ramp-up phase
- Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6-8 hr after the first dose and at each dose increase
- The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities
- 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 initiating
- Reduced renal function (CrCl <80 mL/min) further increases the risk
- Risk may decrease as tumor burden decreases
TSL prophylaxis
- Low tumor burden
- All lymph nodes (LNs) <5 cm AND absolute neutrophil count (ALC) <25 x10^9/L
- Give oral hydration of 1.5-2 L and allopurinol 2-3 days before initiating venetoclax
- Outpatient: Monitor 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 cm to <10 cm OR ALC ≥25 x10^9/L
- Give oral hydration of 1.5-2 L (also consider additional IV hydration) and allopurinol 2-3 days before initiating venetoclax
- Outpatient: Monitor 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 of 20 mg and 50 mg
- 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
- In hospital: Monitor blood chemistry at first dose of 20 mg and 50 mg; predose, 4, 8, 12, and 24 hr
- Outpatient: Monitor blood chemistry at subsequent ramp-up doses; predose, at 6-8 hr, and 24 hr after dose
Acute Myeloid Leukemia (Orphan)
Orphan designation for treatment of acute myeloid leukemia
Sponsor
- AbbVie Inc; 1 Waukegan Road, Dept PA77, Bldg. AP30; North Chicago, Illinois 60044
Multiple Myeloma (Orphan)
Orphan designation for treatment of multiple myeloma
Sponsor
- AbbVie Inc; Regulatory Affairs; 1 North Waukegan Road; North Chicago, Illinois 60064
Pediatric dosage forms and strengths
Safety and efficacy not established
Venclexta (venetoclax) adverse (side) effects
>10%
Neutropenia, any grade (45%)
Neutropenia, grades 3 or 4 (41%)
Diarrhea, any grade (35%)
Nausea, any grade (35%)
Anemia, any grade (29%)
Fatigue, any grade (21%)
Anemia, grades 3 or 4 (18%)
Thrombocytopenia, any grade (22%)
Upper respiratory tract infection, any grade (22%)
Hyperkalemia, any grade (20%)
Pyrexia, any grade (16%)
Thrombocytopenia, grade 3 or 4 (15%)
Hyperphosphatemia, any grade (15%)
Vomiting, any grade (15%)
Headache, any grade (15%)
Constipation, any grade (14%)
Cough, any grade (13%)
Hypokalemia, any grade (12%)
Tumor lysis syndrome, during ramp-up phase and higher doses (12%)
Peripheral edema, any grade (11%)
1-10%
Back pain, any grade (10%)
Hypocalcemia, any grade (9%)
Pneumonia, any grade (8%)
Hyperuricemia, any grade (6%)
Pneumonia, grade 3 or 4 (5%)
Febrile neutropenia, any grade (5%)
Hypokalemia, grade 3 or 4 (4%)
Hyperphosphatemia, grade 3 or 4 (3%)
Hypocalcemia, grade 3 or 4 (3%)
Hyperkalemia, grade 3 or 4 (2%)
Hyperuricemia, grade 3 or 4 (2%)
Fatigue, grade 3 or 4 (2%)
Upper respiratory tract infection, grade 3 or 4 (1%)
<1%
Diarrhea, grade 3 or 4
Nausea, grade 3 or 4
Vomiting, grade 3 or 4
Pyrexia, grade 3 or 4
Peripheral edema, grade 3 or 4
Back pain, grade 3 or 4
Headache, grade 3 or 4
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 (see Dosing Considerations and Dosage modifications)
Neutropenia frequently reported; monitor complete blood counts throughout the treatment period (see Dosage modifications and Adverse effects)
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
- Also see, Dosage modifications, Contraindications, and Drug Interaction Checker
- Venetoclax in 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
- Venetoclax effect on other drugs
- Venetoclax has inhibition potential on P-gp substrates at therapeutic dose levels in the gut; therefore, coadministration of narrow therapeutic index P-gp substrates should be avoided
- 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
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.
Pharmacology of Venclexta (venetoclax)
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
AUC: 32.8 mcg·h/mL
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
Administration
Oral Administration
Take with a meal and water at approximately the same time each day
Tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing
Missed dose
- If the dose is missed within 8 hr of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule
- If a patient misses a dose by >8 hr, the patient should not take the missed dose and should resume the usual dosing schedule the next day
- If the patient vomits following dosing, no additional dose should be taken that day; the next prescribed dose should be taken at the usual time
Storage
Store at or below 86°F (30°C)
