Venetoclax

L01X - Other antineoplastic agents ATC L01XX52 Small molecule approved 2016 Oral First-in-class Natural product

JFDA label: Xervexta

Mechanism of Action

Inhibitor of Apoptosis regulator Bcl-2 — Apoptosis regulator Bcl-2 inhibitor

Target	Action	Gene / class
Apoptosis regulator Bcl-2 efficacy	INHIBITOR	BCL2

Indications

Approved

Chronic lymphocytic leukemia

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Hypersensitivity to venetoclax or any component of the formulation Absolute
Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Very Common Peripheral edema, headache, hyperphosphatemia, hypokalemia

Blood and lymphatic system disorders (2)

Very Common febrile neutropenia · Tumor lysis syndrome

Metabolism and nutrition disorders (2)

Very Common hyperuricemia · Hypocalcemia

Gastrointestinal disorders (1)

Very Common Diarrhea, anemia, thrombocytopenia

Musculoskeletal and connective tissue disorders (1)

Very Common Back pain

General disorders and administration site conditions (1)

Very Common Fever (16%; grades 3/4: 1% to 10%:

Respiratory, thoracic and mediastinal disorders (2)

Very Common cough · Upper respiratory tract infection

Dosing

Source: Lexicomp

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 gradually debulk and 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 3): 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 3): 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 CYP3A 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.

Refer to adult dosing.

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

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).

Warnings & Precautions

Source: Lexicomp

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 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 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. 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.

Pregnancy & Lactation

Pregnancy

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.

Lactation

Avoid

It is not known if venetoclax is excreted in breast milk. Due to the potential for serious adverse reactions in the breast-feeding infant, breast-feeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	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 3) or medium risk (any lymph node 5 to 3): 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.

Clinical pearl

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 3) or medium risk (any lymph node 5 to 3): 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.

Chemistry & Properties

Formula	C45H50ClN7O7S
Molecular weight	868.46 g/mol
IUPAC name	4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
CAS	1257044-40-8
PubChem CID	49846579
InChIKey	`LQBVNQSMGBZMKD-UHFFFAOYSA-N`
logP	8.66 (XLogP 8.2)
Polar surface area	172.03 Å²
H-bond acceptors / donors	11 / 3
Drug-likeness (QED)	0.08
Lipinski violations	3

SMILES

CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	0.671 h
Volume of distribution	0.982 L/kg
Protein binding	99.6%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	IC₅₀ 1.770000000000001 µM
CYP2C9	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 4)

Target	Action	Affinity
BCL2 apoptosis regulator (BCL2)	Antagonist	pKi 11.0
Bcl-2-like 1 (BCL2L1)	Antagonist	pKi 7.3
Bcl-2-like 2 (BCL2L2)	Antagonist	pKi 6.6
MCL1 apoptosis regulator, BCL2 family member (MCL1)	Antagonist	pKi 6.3

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abiraterone	major
Adalimumab	major
Amiodarone	major
Amprenavir	major
Apalutamide	major
Aprepitant	major
Atazanavir	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Bepridil	major
Berotralstat	major
Boceprevir	major
Bosentan	major
Cabozantinib	major
Capmatinib	major
Captopril	major
Carbamazepine	major
Carvedilol	major
Cenobamate	major
Ceritinib	major
Certolizumab pegol	major
Ciprofloxacin	major
Cladribine	major
Clarithromycin	major
Clozapine	major
Cobicistat	major
Colchicine	major
Conivaptan	major
Crizotinib	major
Cyclosporine	major
Dabrafenib	major
Daclatasvir	major
Dalfopristin	major
Darunavir	major
Deferiprone	major
Delavirdine	major
Dexamethasone	major
Diltiazem	major
Dronedarone	major
Duvelisib	major

Showing 40 of 100+.

Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Xervexta	Tablet 100 mg	120 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Xervexta	Tablet 10, 50, 100 mg	10 mg	HIKMA PHARMACEUTICALS - JORDAN	—
venclexta	Tablet 100 mg	120 tab	Abu Sheikha Drug Store	—
venclexta Starter Dose	Tablet 10, 50, 100 mg	42 tab	Abu Sheikha Drug Store	—