eadache 15 <1
Respiratory, thoracic, and
mediastinal disorders Cough 13 0
Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0.
aNeutropenia/neutrophil count decreased.
bAnemia/hemoglobin decreased.
cThrombocytopenia/platelet count decreased.
Tumor Lysis Syndrome
Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA. In the initial Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting dose, the incidence of TLS was 12% (9/77; 4 laboratory TLS, 5 clinical TLS), including 2 fatal events and 3 events of acute renal failure, 1 requiring dialysis.
The risk of TLS was reduced after revision of the dosing regimen and modification to prophylaxis and monitoring measures [see Dosage and Administration (2.2, 2.3)]. In venetoclax clinical trials, patients with any measurable lymph node ≥10 cm or those with both an ALC ≥25 x 109/L and any measurable lymph node ≥5 cm were hospitalized to enable more intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the ramp-up phase.
In 66 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg, the rate of TLS was 6%. All events either met laboratory TLS criteria (laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L); or were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm or ALC ≥25 x 109/L. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias or sudden death and/or seizures was observed in these patients. All patients had CrCl ≥50 mL/min.
Laboratory abnormalities relevant to TLS observed in 66 patients with CLL who followed the dose ramp-up schedule and TLS prophylaxis measures are presented in Table 8.
Table 8. Adverse Reactions of TLS and Relevant Laboratory Abnormalities Reported in Patients with CLL Parameter All Grades (%)
N=66 Grade ≥3 (%)
N=66
Laboratory TLSa 6 6
Hyperkalemiab 20 2
Hyperphosphatemiac 15 3
Hypocalcemiad 9 3
Hyperuricemiae 6 2
aLaboratory abnormalities that met ≥2 of the following criteria within 24 hours of each other: potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L; or were reported as TLS events.
bHyperkalemia/blood potassium increased.
cHyperphosphatemia/blood phosphorus increased.
dHypocalcemia/blood calcium decreased.
eHyperuricemia/blood uric acid increased.
7 DRUG INTERACTIONS
7.1 Effects of Other Drugs on VENCLEXTAVenetoclax is predominantly metabolized by CYP3A4/5.
Strong CYP3A Inhibitors
Concomitant use of VENCLEXTA with strong CYP3A inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, lopinavir, ritonavir, telaprevir, posaconazole and voriconazole) at initiation and during ramp-up phase is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3)].
For patients who have completed the ramp-up phase and are on a steady daily dose of VENCLEXTA, reduce the VENCLEXTA dose by at least 75% when used concomitantly with strong CYP3A inhibitors. Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Admin |
