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Venclexta Dosage

Generic name: Venetoclax 10mg; Venetoclax 50mg; Venetoclax 100mg
Dosage form: tablets

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Patient Selection

Select patients for the treatment of relapsed or refractory CLL with VENCLEXTA based on the presence of 17p deletions in blood specimens [see Indications and Usage (1) and Clinical Studies (14)]. Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur. Information on FDA-approved tests for the detection of 17p deletions in CLL is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to reduce risk of TLS [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Administer the VENCLEXTA dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg as shown in Table 1. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.

Instruct patients to take VENCLEXTA tablets with a meal and water at approximately the same time each day. VENCLEXTA tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Table 1. Dosing Schedule for Ramp-Up Phase
Week VENCLEXTA
Daily Dose
1 20 mg
2 50 mg
3 100 mg
4 200 mg
5 and beyond 400 mg

The Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule. Once the ramp-up phase is completed, the 400 mg dose is achieved using 100 mg tablets supplied in bottles [see How Supplied/Storage and Handling (16)].

VENCLEXTA should be taken orally once daily until disease progression or unacceptable toxicity is observed.

Risk Assessment and Prophylaxis for Tumor Lysis Syndrome

VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA 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 (e.g., CT scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA. Reduced renal function (creatinine clearance [CrCl] <80 mL/min) further increases the risk. The risk may decrease as tumor burden decreases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Table 2 below describes the recommended TLS prophylaxis and monitoring during VENCLEXTA treatment based on tumor burden determination from clinical trial data.

Table 2. Recommended TLS Prophylaxis Based on Tumor Burden From Clinical Trial Data (consider all patient co-morbidities before final determination of prophylaxis and monitoring schedule)
Tumor Burden Prophylaxis Blood Chemistry
Monitoringc,d
  Hydrationa Anti-hyperuricemics Setting and
Frequency of
Assessments
Low All LN <5 cm AND
ALC <25 x109/L
Oral
(1.5-2 L)
Allopurinolb Outpatient
  • Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg
  • Pre-dose at subsequent ramp-up doses
Medium Any LN 5 cm to <10 cm
OR
ALC ≥25 x109/L
Oral
(1.5-2 L)
and consider additional intravenous
Allopurinol Outpatient
  • Pre-dose, 6 to 8 hours, 24 hours at first dose of 20 mg and 50 mg
  • Pre-dose at subsequent ramp-up doses
  • Consider hospitalization for patients with CrCl <80ml/min at first dose of 20 mg and 50 mg; see below for monitoring in hospital
High Any LN ≥10 cm OR
ALC ≥25 x109/L AND
any LN ≥5 cm
Oral (1.5-2L)
and intravenous
(150-200 mL/hr
as tolerated)
Allopurinol; consider rasburicase if baseline uric acid is elevated In hospital at first dose of 20 mg and 50 mg
  • Pre-dose, 4, 8,12 and 24 hours
Outpatient at subsequent ramp-up doses
  • Pre-dose, 6 to 8 hours, 24 hours
ALC = absolute lymphocyte count; LN = lymph node.
aAdminister intravenous hydration for any patient who cannot tolerate oral hydration.
bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA.
cEvaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.
dFor patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose.

Dose Modifications Based on Toxicities

Interrupt dosing or reduce dose for toxicities. See Table 3 for dose modifications for hematologic and other toxicities related to VENCLEXTA, and Table 4 for dose. For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks when at the daily dose of 400 mg, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule) [see Dosage and Administration (2.2, 2.3)].

Table 3. Recommended Dose Modifications for Toxicitiesa
Event Occurrence Action
Tumor Lysis Syndrome
Blood chemistry changes or symptoms suggestive of TLS Any Withhold the next day’s dose. If resolved within 24 to 48 hours of last dose, resume at the same dose.
For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 4) [see Dosage and Administration (2.3)].    
For any events of clinical TLS,b resume at a reduced dose following resolution (see Table 4) [see Dosage and Administration (2.3)].    
Non-Hematologic Toxicities
Grade 3 or 4 non-hematologic toxicities 1st occurrence Interrupt VENCLEXTA.
Once the toxicity has resolved to Grade 1 or baseline level, VENCLEXTA therapy may be resumed at the same dose. No dose modification is required.
2nd and subsequent occurrences Interrupt VENCLEXTA.
Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTA after resolution. A larger dose reduction may occur at the discretion of the physician.
 
Hematologic Toxicities
Grade 3 or 4 neutropenia with infection or fever; or Grade 4 hematologic toxicities (except lymphopenia) [see Warnings and Precautions (5.2)] 1st occurrence Interrupt VENCLEXTA.
To reduce the infection risks associated with neutropenia, granulocyte-colony stimulating factor (G-CSF) may be administered with VENCLEXTA if clinically indicated. Once the toxicity has resolved to Grade 1 or baseline level, VENCLEXTA therapy may be resumed at the same dose.
2nd and subsequent occurrences Interrupt VENCLEXTA.
Consider using G-CSF as clinically indicated.
Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTA after resolution. A larger dose reduction may occur at the discretion of the physician.
 
Consider discontinuing VENCLEXTA for patients who require dose reductions to less than 100 mg for more than 2 weeks.
aAdverse reactions were graded using NCI CTCAE version 4.0.
bClinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures.
Table 4. Dose Modification for Toxicity During VENCLEXTA Treatment
Dose at Interruption, mg Restart Dose, mga
400 300
300 200
200 100
100 50
50 20
20 10
aDuring the ramp-up phase, continue the reduced dose for 1 week before increasing the dose.

Dose Modifications for Use with CYP3A and P-gp Inhibitors

Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. Concomitant use of VENCLEXTA with strong CYP3A inhibitors increases venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during ramp-up phase [see Contraindications (4)]. 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 strong CYP3A inhibitors must be used concomitantly.

Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors or P-gp inhibitors. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the VENCLEXTA dose by at least 50%. Monitor these patients more closely for signs of toxicities [see Dosage and Administration (2.4)].

Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

The recommendations for managing drug-drug interactions are summarized in Table 5.

Table 5. Management of Potential VENCLEXTA Interactions with CYP3A and P-gp Inhibitors
Inhibitors Initiation and Ramp-Up
Phase
Steady Daily Dose
(After Ramp-Up Phase)
Strong CYP3A inhibitor Contraindicated Avoid inhibitor use or reduce the VENCLEXTA dose by at least 75%
Moderate CYP3A inhibitor Avoid inhibitor use or reduce the VENCLEXTA dose by at least 50%
P-gp inhibitor    

Missed Dose

If the patient misses a dose of VENCLEXTA within 8 hours 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 more than 8 hours, 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.

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