Venetoclax

Venetoclax

Therapeutic indication

adult CLL patients

Mechanism of action

Venetoclax is a potent, selective inhibitor of B cell lymphoma (BCL) 2, an anti-apoptotic protein. Overexpression of BCL 2 has been demonstrated in CLL cells where it mediates tumour cell survival and has been associated with resistance to chemotherapeutics. Venetoclax binds directly to the BH3 binding groove of BCL 2, displacing BH3 motif-containing pro apoptotic proteins like BIM, to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and programmed cell death. In non clinical studies, venetoclax has demonstrated cytotoxic activity in tumour cells that overexpress BCL 2.

Venetoclax Fiche BHS

Treatment schemes for R/R CLL(1)

 
Dosage
Days(D)/weeks(w)
Cycles
Venetoclax
(recommended with meal)
20 mg/d, once daily
50 mg/d, once daily
100 mg/d, once daily
200 mg/d, once daily
400 mg/d, once daily
D1-7
D7-14
D14-21
D21-28
D28 - ….
Continuous treatment until disease progression or intolerance


Indications and reimbursement (1) (2)

As of the 1st of november, venetoclax in monotherapy is reimbursed in the following indications for adult CLL patients :
Without 17p deletion or TP53 mutation who have failed both chemoimmunotherapy and a B-cell receptor inhibitor (BCRi)
With 17p deletion or TP53 mutation who have failed a BCRi
With 17p deletion or TP53 mutation who are unsuitable for a BCRi
The reimbursement approval has to be done via the eHealth platform https://www.ehealth.fgov.be


Mode of action (1) 

Venetoclax is a potent, selective inhibitor of B‑cell lymphoma (BCL)‑2, an anti-apoptotic protein. Overexpression of BCL‑2 has been demonstrated in CLL cells where it mediates tumour cell survival and has been associated with resistance to chemotherapeutics. Venetoclax binds directly to the BH3‑binding groove of BCL‑2, displacing BH3 motif-containing pro‑apoptotic proteins like BIM, to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and programmed cell death. In non‑clinical studies, venetoclax has demonstrated cytotoxic activity in tumour cells that overexpress BCL‑2.


Special Populations(1)

Elderly
No specific dose adjustment is required for elderly patients (>65 years)
Renal impairment
  • Severe renal impairment(CrCl <30 mL/min or on dialysis) A recommended dose has not been determined. Only administer venetoclax if the benefit outweighs the risk and monitor closely for signs of toxicity caused by increased risk of TLS
  • Mild or moderate renal impairment (CrCl ≥30 mL/min and <90 mL/min) No dose adjustment is recommended. Patients may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation of treatment with venetoclax and during the dose-titration phase
Hepatic impairment
  • Severe hepatic impairment. Administration of venetoclax is not recommended
  • Mild or moderate hepatic impairment. No dose adjustment is recommended. Patients should be monitored more closely for signs of toxicity at initiation of treatment with venetoclax and during the dose-titration phase
Pediatric population
The safety and efficacy of venetoclax in children aged <18 years have not been established (no data are available)

Venetoclax drug interactions(1)

Venetoclax ö
Strong CYP3A inhibitors
Moderate CYP3A inhibitors
P-gp and BCRP inhibitors
Clarithromycin
Aprepitant
Geftinib
Telithromycin
Ciprofloxacin
Cyclosporine
Ketoconazole
Erythromycin
Amiodarone
Itraconazole
Fluconazole
Felodipine
Posaconazole
Diltiazem

Voriconazole
Verapamil

HIV medication (ritonavir, ..)
Amiodarone

Grape fruit (juice)/ sevilla orange/ starfruit


Dose adjustments for use with CYP3A inhibitors

Initiation and titration phase
Strong CYP3A inhibitors are strictly contraindicated in the initiation and titration phase
Moderate CYP3A inhibitors should be avoided in the initiation and titration phase. If a moderate CYP3A inhibitor must be used, the initiation and titration doses of Venetoclax should be reduced by at least 50%. Patients should be monitored more closely for signs of toxicities
During the steady-state dosing treatment
The Venetoclax dose should be reduced by 50% when used concomitantly with moderate CYP3A inhibitors and by 75% when used concomitantly with strong CYP3A inhibitors. Patients should be monitored more closely for signs of toxicities, and the dose may need to be further adjusted. The Venetoclax dose that was used prior to initiating the CYP3A inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor
Venetoclax ø
CYP3A inducers 
Bile acid sequestrants
Carbamazepine

Phenytoin

Rifampicin

Rifabutin

Phenobarbital

Dexamethazone

St John’s wort

Agents that may have their plasma concentration altered by venetoclax
Warfarin
Substrates of P-gp, BCRP, and OATP1B1

Digoxine

Everolimus

Dabigatran

Sirolimus

Statines





Contraindications Venetoclax(1)

Hypersensitivity to the active substance or to any of the excipients
Concomitant use of strong CYP3A inhibitors at initiation and during the dose titration phase
Concomitant use of preparations containing St. John’s wort


Venetoclax: Prophylaxis /monitoring of Tumor Lysis syndrome(1)(3)

TLS Risk:
Low
Intermediate 
High
Hydratation
Ensure adequate hydration throughout dose-titration, particularly 2 days prior to and the days of dosing at initiation and each subsequent dose increase; IV fluids based on TLS risk or who cannot maintain adequate oral hydration.
Oral (1.5 -2 L)
Oral (1.5 - 2 L) and consider additional IV if tolerated
Oral (1.5 - 2 L) and IV (150-200 mL/hr as tolerated
Anti-hyperuricemic agents
 
Start anti-hyperuricemic agents 2 to 3 days prior to first dose, which may be continued through the titration phase based on the ongoing risk of TLS. Subjects allergic to allopurinol must use another uric acid reducer.
Anti hyperuricaemic agent (e.g., allopurinol)
Anti hyperuricaemic agent (e.g., allopurinol)
Anti hyperuricaemic agent
(If available, consider rasburicase if baseline uric acid is elevated)
Blood chemistry monitoring
Correct pre-existing blood chemistry abnormalities prior to initiation of treatment. Monitor blood chemistry in real time (turn around < 2 hrs): potassium, uric acid, phosphorus, calcium, and creatinine
Outpatient Monitoring
Pre-dose, 6-8, 24 hrs* (at 1st dose of 20 mg and 50 mg)
Pre-dose at subsequent ramp-up doses
 
Outpatient Monitoring
Pre-dose, 6-8, 24 hrs* (at 1st dose of 20 mg and 50 mg)
Pre-dose at subsequent ramp-up doses
Consider hospitalization if CrCl < 80ml/min at 1st dose of 20 mg and 50 mg
 
In hospital Monitoring
(1st dose of 20 and 50 mg)
Pre-dose, 4, 8, 12, 24 hrs*
Outpatient Monitoring
(subsequent ramp-up doses)
Pre-dose, 6-8, 24 hrs*
 
*24 hrs labs: Do not administer the next dose until 24-hour blood chemistry results have been evaluated.






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