Venclexta (venetoclax)

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What is Venclexta, and how does it work?

Venclexta is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
  • are 75 years of age or older, or
  • have other medical conditions that prevent the use of standard chemotherapy.

It is not known if
Venclexta is safe and effective in children.

What are the side effects of Venclexta?

Venclexta can cause serious side effects, including:

• Low white blood cell count (neutropenia). Low white blood cell counts are common with
  Venclexta but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with
  Venclexta.
• Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with
  Venclexta. Your healthcare provider will closely monitor and treat you right away if you have fever or any signs of infection during treatment with
  Venclexta.

Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with
Venclexta.

The most common side effects of Venclexta when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include:

• low platelet counts
• low red blood cell counts
• diarrhea
• nausea
• upper respiratory tract infection
• cough
• muscle and joint pain
• tiredness
• swelling of your arms, legs, hands, and feet

The most common side effects of
Venclexta in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include:

• nausea
• diarrhea
• low platelet counts
• constipation
• fever with low white blood cell counts
• low red blood cell counts
• infection in blood
• rash
• dizziness
• low blood pressure
• fever
• swelling of your arms, legs, hands, and feet
• vomiting
• tiredness
• shortness of breath
• bleeding
• infection in lung
• stomach (abdominal) pain
• pain in muscles or back
• cough
• sore throat

Venclexta may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of
Venclexta. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.

What is the dosage for Venclexta?

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.
• 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.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Venclexta dosing begins with a 5-week ramp-up.
• Venclexta 5-week Dose Ramp-Up Schedule
• 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.

Table 1. Dosing Schedule for Ramp-Up Phase in Patients with CLL/SLL

Venclexta
Daily DoseWeek 120 mgWeek 250 mgWeek 3100 mgWeek 4200 mgWeek 5 and beyond400 mg

• The CLL/SLL Starting Pack provides the first 4 weeks of Venclexta
  according to the ramp-up schedule. The 400 mg dose is achieved using 100 mg
  tablets supplied in bottles.

Venclexta in Combination with Obinutuzumab

• Start obinutuzumab administration at 100 mg on Cycle 1 Day 1, followed by 900 mg on Cycle 1 Day 2.
• Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28day cycle, for a total of 6 cycles.
• Refer to the obinutuzumab prescribing information for recommended obinutuzumab dosing information.
• On Cycle 1 Day 22, start Venclexta according to the 5-week ramp-up schedule (see Table 1).
• After completing the ramp-up schedule on Cycle 2 Day 28, patients should continue
  Venclexta 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12.

Venclexta in Combination with Rituximab

• Start rituximab administration after the patient has completed the 5-week dose ramp-up schedule with
  Venclexta (see Table 1) and has received the 400 mg dose of Venclexta for 7 days.
• Administer rituximab on Day 1 of each 28-day cycle for 6 cycles, with rituximab dosed at 375 mg/m² intravenously for Cycle 1 and 500 mg/m² intravenously for Cycles 2-6.
• Patients should continue Venclexta 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab.

Venclexta as Monotherapy

• The recommended dose of Venclexta is 400 mg once daily after the patient has completed the 5-week dose ramp-up schedule.
• Venclexta should be taken orally once daily until disease progression or unacceptable toxicity is observed.
• The dose of Venclexta depends upon the combination agent.
• The Venclexta dosing schedule (including ramp-up) is shown in Table 2. Initiate the azacitidine or decitabine or low-dose cytarabine on Day 1.

Table 2. Dosing Schedule for Ramp-up Phase in Patients with AML

Venclexta
Daily DoseDay 1100 mgDay 2200 mgDay 3400 mgDays 4 and beyond400 mg when dosing in combination with azacitidine or decitabine600 mg when dosing in combination with low-dose cytarabine

• Continue Venclexta, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity is observed.

Risk Assessment And Prophylaxis For Tumor Lysis Syndrome

• Patients treated with Venclexta may develop tumor lysis syndrome.
• Refer to the appropriate section below for specific details on management.
• 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.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Venclexta 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 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. Reduced renal function (creatinine clearance [CLcr] <80
  mL/min) further increases the risk.
• 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.
• The
  risk may decrease as tumor burden decreases.
• Table 3 below describes the recommended TLS prophylaxis and monitoring during
  Venclexta treatment based on tumor burden determination from clinical trial data. Consider all patient comorbidities before final determination of prophylaxis and monitoring schedule.

Table 3. Recommended TLS Prophylaxis Based on Tumor Burden in Patients with CLL/SLL

Tumor BurdenProphylaxisBlood Chemistry Monitoring^c,dHydration^aAntihyperuricemicsSetting and Frequency of AssessmentsLowAll LN <5 cm
AND
ALC <25 x 10⁹/LOral
(1.5-2 L)Allopurinol^bOutpatient

• For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours
• For subsequent ramp-up doses: Pre-dose

MediumAny LN 5 cm to <10 cm
OR
ALC ≥25 x10⁹/LOral
(1.5-2 L)
and consider additional intravenousAllopurinolOutpatient

• For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours
• For subsequent ramp-up doses: Pre-dose
• For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CLcr <80ml/min; see below for monitoring in hospital

HighAny LN ≥10 cm
OR
ALC ≥25 x10⁹/L
AND
any LN ≥5 cmOral (1.5-2 L) and intravenous (150-200 mL/hr as tolerated)Allopurinol; consider rasburicase if baseline uric acid is elevatedIn hospital

• For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours

Outpatient

• For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours

ALC = absolute lymphocyte count; CLcr = creatinine clearance; 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.

Acute Myeloid Leukemia

• All patients should have white blood cell count less than 25 × 10⁹/L prior to initiation of
  Venclexta. Cytoreduction prior to treatment may be required.
• Prior to first
  Venclexta dose, provide all patients with prophylactic measures including adequate hydration and anti-hyperuricemic agents and continue during ramp-up phase.
• Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with
  Venclexta.
• Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during ramp-up and 24 hours after reaching final dose.
• For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase (LDH) levels, or reduced renal function) additional measures should be considered, including increased laboratory monitoring and reducing
  Venclexta starting dose.

Dosage Modifications Based On Toxicities

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Interrupt dosing or reduce dose for toxicities. See Table 4 and Table 5 for
  recommended dose modifications for toxicities related to Venclexta.
• 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 after completing the ramp-up phase,
  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).

Table 4. Recommended Venclexta Dose Modifications for Toxicities^a in CLL/SLL

EventOccurrenceActionTumor Lysis SyndromeBlood chemistry changes or symptoms suggestive of TLSAnyWithhold 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 5).For any events of clinical TLS,^b
resume at a reduced dose following resolution (see Table 5).Non-Hematologic ToxicitiesGrade 3 or 4 non-hematologic toxicities1^st occurrenceInterrupt
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.2^nd and subsequent occurrencesInterrupt
Venclexta. Follow dose reduction guidelines in Table 5 when resuming treatment with
Venclexta after resolution. A larger dose reduction may occur at the discretion of the physician.Hematologic ToxicitiesGrade 3 neutropenia with infection or fever; or Grade 4 hematologic toxicities
(except lymphopenia)1^st occurrenceInterrupt
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.2^nd and subsequent occurrencesInterrupt
Venclexta. Consider using G-CSF as clinically indicated. Follow dose reduction guidelines in Table 5 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 5. Dose Reduction for Toxicity During
Venclexta Treatment in CLL/SLL

Dose at Interruption, mgRestart Dose, mg^a4003003002002001001005050202010^aDuring the ramp-up phase, continue the reduced dose for 1 week before increasing the dose.

Monitor blood counts frequently through resolution of cytopenias. Management of
some adverse reactions may require dose interruptions or permanent discontinuation of
Venclexta. Table 6 shows the dose modification guidelines for hematologic toxicities.

Table 6. Recommended Dose Modifications for Toxicities^a in AML

EventOccurrenceActionHematologic ToxicitiesGrade 4 neutropenia with or without fever or infection; or Grade 4
thrombocytopeniaOccurrence prior to achieving remissionTransfuse blood products, administer prophylactic and treatment anti-infectives as clinically indicated.In most instances,
Venclexta and azacitidine, decitabine, or low-dose cytarabine cycles should not be interrupted due to cytopenias prior to achieving remission.First occurrence after achieving remission and lasting at least 7 daysDelay subsequent treatment cycle of
Venclexta and azacitidine, decitabine, or low-dose cytarabine and monitor blood counts.Administer granulocyte-colony stimulating factor (G-CSF) if clinically indicated for neutropenia. Once the toxicity has resolved to Grade 1 or 2, resume
Venclexta therapy at the same dose in combination with azacitidine or decitabine or low-dose cytarabine.Subsequent occurrences in cycles after achieving remission and lasting 7 days or longerDelay subsequent treatment cycle of
Venclexta and azacitidine, or decitabine, or low-dose cytarabine and monitor blood counts.Administer G-CSF if clinically indicated for neutropenia. Once the toxicity has resolved to Grade 1 or 2, resume
Venclexta therapy at the same dose and the duration reduced by 7 days for each subsequent cycle.^aAdverse reactions were graded using NCI CTCAE version 4.0.

Dosage Modifications For Concomitant Use With Strong Or Moderate CYP3A Inhibitors Or P-gp Inhibitors

Table 7 describes Venclexta contraindication or dosage modification based on
concomitant use with a strong or moderate CYP3A inhibitor or P-gp inhibitor at initiation, during, or after the ramp-up phase.

Resume the Venclexta dosage that was used prior to concomitant use of a strong
or moderate CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation
of the inhibitor.

Table 7. Management of Potential
Venclexta Interactions with CYP3A and P-gp Inhibitors

Coadministered drugInitiation and Ramp-Up PhaseSteady Daily Dose
(After Ramp-Up Phase)^aPosaconazoleCLL/SLLContraindicatedReduce
Venclexta dose to 70 mg.AMLDay 1 – 10 mgDay 2 – 20 mgDay 3 – 50 mgDay 4 – 70 mgOther strong CYP3A inhibitorCLL/SLLContraindicatedReduce
Venclexta dose to 100 mg.AMLDay 1 – 10 mgDay 2 – 20 mgDay 3 – 50 mgDay 4 – 100 mgModerate CYP3A inhibitorReduce the
Venclexta dose by at least 50%.P-gp inhibitor^aIn patients with CLL/SLL, consider alternative medications or reduce the
Venclexta dose as described in Table 7.

Dosage Modifications For Patients With Severe Hepatic Impairment

• Reduce the Venclexta once daily dose by 50% for patients with severe hepatic
  impairment (Child-Pugh C); monitor these patients more closely for signs of
  toxicity.

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.

What drugs interact with Venclexta?

Effects Of Other Drugs On Venclexta

Strong Or Moderate CYP3A Inhibitors Or P-gp Inhibitors

• Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp
  inhibitor increases venetoclax Cmax and AUCinf, which may increase Venclexta
  toxicities, including the risk of TLS.
• Concomitant use with a strong CYP3A inhibitor at initiation and during
  the ramp-up phase in patients with CLL/SLL is contraindicated.
• In patients with CLL/SLL taking a steady daily dosage (after ramp-up
  phase), consider alternative medications or adjust Venclexta dosage and
  closely monitor for signs of Venclexta toxicities.
• In patients with AML, adjust Venclexta dosage and closely monitor for
  signs of Venclexta toxicities.
• Resume the Venclexta dosage that was used prior to concomitant use with
  a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after
  discontinuation of the inhibitor.
• Avoid grapefruit products, Seville oranges, and starfruit during treatment with
  Venclexta, as they contain inhibitors of CYP3A.

Strong Or Moderate CYP3A Inducers

• Concomitant use with a strong CYP3A inducer decreases venetoclax Cmax
  and AUCinf, which may decrease Venclexta efficacy.
• Avoid concomitant use of Venclexta with strong CYP3A inducers or moderate CYP3A inducers.

Effect Of Venclexta On Other Drugs

Warfarin

• Concomitant use of Venclexta increases warfarin Cmax and AUCinf, which may increase the risk of bleeding. Closely monitor international normalized ratio (INR) in patients using warfarin concomitantly with
  Venclexta.

P-gp Substrates

• Concomitant use of Venclexta increases Cmax and AUCinf of P-gp
  substrates, which may increase toxicities of these substrates.
• Avoid concomitant use of Venclexta with a P-gp substrate.
• If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before
  Venclexta.

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Is Venclexta safe to use while pregnant or breastfeeding?

• There are no available data on Venclexta use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.
• Based on toxicity observed in mice, Venclexta may cause fetal harm when administered to pregnant women.
• In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at a human dose of 400 mg daily.
• Advise pregnant women of the potential risk to a fetus.
• There are no data on the presence of Venclexta in human milk, the effects of
  Venclexta on the breastfed child, or the effects of Venclexta on milk production.
• Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from
  Venclexta is unknown, advise nursing women to discontinue breastfeeding during treatment with
  Venclexta.