Venetoclax is a medicine that targets a protein called BCL-2, which is too high in certain types of leukemia cells. It is used to treat chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML).

It is used to treat the following conditions:

• Acute myeloid leukemia:
  • Venetoclax is used along with other drugs (azacitidine, decitabine, or low-dose cytarabine) to treat newly-diagnosed acute myeloid leukemia in patients who are over 75 years old or have other medical conditions that require intensive chemotherapy.
• Chronic lymphocytic leukemia and small lymphocytic lymphoma:
  • Venetoclax is used to treat chronic lymphocytic leukemia and small lymphocytic lymphoma in adults.
• Off Label Usage of Venetoclax in Adults:
  • Venetoclax is sometimes used as an off-label treatment for mantle cell lymphoma.

Venetoclax Dose in Adults

Note: Before starting treatment with Venetoclax, doctors should evaluate the patient's risk for tumor lysis syndrome, a condition that can occur when cancer cells die too quickly and release their contents into the bloodstream. To prevent this, patients should receive prophylactic hydration and anti-hyperuricemic medication to help the body eliminate these substances.

Dose in the treatment of Newly diagnosed Acute myeloid leukemia: Adults ≥75 years of age or with comorbidities:  

The recommended dosing schedule for Venetoclax in the treatment of newly diagnosed acute myeloid leukemia in adults who are 75 years of age or older or have comorbidities is as follows:

• Start azacitidine, decitabine, or low-dose cytarabine on the first day of treatment.
• The dose of Venetoclax may depend on the chemotherapy agent used alongside it.
• The patient's white blood cell count should be less than 25,000/mm before starting Venetoclax.
• Cytoreduction (reducing the number of cancer cells) before the treatment may be necessary.

The recommended dosing schedule for Venetoclax is as follows:

• On day first take 100 mg by mouth once a day.
• On second day take 200 mg by mouth once a day.
• On third day take 400 mg by mouth once a day.

• For patients receiving Venetoclax in combination with azacitidine or decitabine, the recommended dose from Day 4 onwards is 400 mg taken by mouth once a day until disease progression or unacceptable toxicity occurs.
• For patients receiving Venetoclax in combination with low-dose cytarabine, the recommended dose from Day 4 onwards is 600 mg taken by mouth once a day until disease progression or unacceptable toxicity occurs.

Dose in the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma: 

The recommended dosing regimen for Venetoclax in the treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma is:

• On first week the recommended dose is 20 mg taken by mouth once a day.
• On second week the recommended dose is 50 mg taken by mouth once a day.
• On third week the recommended dose is 100 mg taken by mouth once a day.
• On fourth week the recommended dose is 200 mg taken by mouth once a day.
• On fifth week the recommended dose is 400 mg taken by mouth once a day.
• From fifth Weeks  onwards, the recommended dose is 400 mg orally once a day, and treatment is continued until disease progression or unacceptable toxicity occurs.

Venetoclax in combination with obinutuzumab:

• When used in combination with Obinutuzumab, Obinutuzumab is started on day 1 of cycle 1, and Venetoclax is started on day 22 of cycle 1 according to the 5-week schedule for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma mentioned above.
• The ramp-up is completed at the end of cycle 2, and from cycle 3 onwards, Venetoclax is given at a dose of 400 mg orally once a day until the end of cycle 12. Each cycle is 4 weeks.

Venclexta in combination with rituximab: Week 5 and thereafter:

• When used in combination with Rituximab, Venetoclax is given at a dose of 400 mg orally once a day from week 5 onwards. Treatment with Venetoclax is continued until disease progression or unacceptable toxicity occurs, for up to 2 years from day 1 (cycle 1) of rituximab.
• Rituximab should be started after receiving Venetoclax at the 400 mg once daily dose for 1 week, and premedication with I/V fluids and anti-hyperuricemic therapy is recommended.

Dose in the treatment of Acute myeloid leukemia:

• White blood cell count should be less than 25,000/mm before starting venetoclax.
• Cytoreduction may be necessary before treatment.
• Adequate hydration and anti-hyperuricemic agents should be given
• Electrolyte abnormalities should be corrected before treatment
• For patients at high risk of TLS, additional preventive measures should be taken
• Laboratory monitoring should be increased
• Initial venetoclax doses should be reduced for high-risk patients.

Dosage in the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma:

For patients with low tumor burden chronic lymphocytic leukemia/small lymphocytic lymphoma, outpatient management is appropriate.

The following steps are recommended:

• Oral hydration with 1.5 to 2 L of fluid intake
• Administer allopurinol 2 to 3 days before starting venetoclax initiation.
• Administer Intravenous (IV) hydration for patients unable to tolerate oral hydration.

For patients with medium tumor burden (any lymph node 5 to <10 cm or ALC ≥25,000/mm), the following measures are recommended for outpatient management:

• Oral hydration with 1.5 to 2 L of fluid intake
• Allopurinol administration starting 2 to 3 days before venetoclax initiation
• Intravenous (IV) hydration for patients who cannot tolerate oral hydration

For patients with high tumor burden (any lymph node ≥10 cm OR ALC ≥25,000/mm and any lymph node ≥5 cm):

• The initial ramp-up phase of venetoclax should be completed in an inpatient setting.
• The patient should receive hydration of 1.5 to 2 L orally and 150 to 200 mL/hour IV hydration if oral hydration is not tolerated.
• Allopurinol should be administered starting 2 to 3 days before venetoclax initiation, and rasburicase should be used if the baseline uric acid level is increased.
• If clinically indicated, the ramp-up phase can be completed on an outpatient basis.

Off-label Dosage of Venetoclax in Refractory or Relapsed Mantle Cell Lymphoma:

Venetoclax Monotherapy:

• On first week the recommended dose is 20mg taken by mouth once a day.
• On second week the recommended dose is 50mg taken by mouth once a day
• On third week the recommended dose is 100mg taken by mouth once a day
• On fourth week the recommended dose is 200mg taken by mouth once a day
• On fifth week the recommended dose is 400mg taken by mouth once a day
• On sixth week or onwards the recommended dose is 800mg once a day until disease progression, unacceptable toxicity or allogeneic stem cell transplant

Venetoclax in Combination with Ibrutinib:

• Venetoclax is started after 1 month of ibrutinib monotherapy to reduce the risk of tumor lysis syndrome.
• On week fifth the recommended dose is 20mg taken by mouth once a day
• On week sixth the recommended dose is 50mg taken by mouth once a day
• On week seventh the recommended dose is 100mg taken by mouth once a day
• On week eight the recommended dose is 200mg taken by mouth once a day
• On week ninth or onwards the recommended dose is 400mg once a day until disease progression or unacceptable toxicity
• Venetoclax dose can be increased to 800mg once a day after week 16 if complete response hasn't occurred

Dosage adjustment of Venclexta for concomitant strong or moderate CYP3A inhibitors or P-GP inhibitors:

For chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), the recommended dose adjustment for Venclexta with concomitant strong or moderate CYP3A inhibitors or P-GP inhibitors is as follows:

• Strong CYP3A inhibitors or P-GP inhibitors: Reduce Venclexta dose to 70 mg once daily during ramp-up phase and 100 mg once daily during maintenance phase.
• Moderate CYP3A inhibitors or P-GP inhibitors: Reduce Venclexta dose to 100 mg once daily during ramp-up phase and 200 mg once daily during maintenance phase.

For acute myeloid leukemia (AML), the recommended dose adjustment for Venclexta with concomitant strong or moderate CYP3A inhibitors or P-GP inhibitors is as follows:

• Strong CYP3A inhibitors or P-GP inhibitors: Reduce Venclexta dose to 70 mg once daily during ramp-up phase and 100 mg once daily during maintenance phase.
• Moderate CYP3A inhibitors or P-GP inhibitors: Reduce Venclexta dose to 200 mg once daily during ramp-up phase and 400 mg once daily during maintenance phase.

Dosage adjustment of Venclexta for strong CYP3A inhibitors (other than posaconazole):

• If you need to take a strong CYP3A inhibitor with venetoclax, you'll need a reduced ramp-up dosing schedule.
• On first day take 10 mg of venetoclax
• On second day take 20 mg of venetoclax
• On third day take 50 mg of venetoclax
• On fourth day and after take 100 mg of venetoclax
• If you're also taking posaconazole, lower your venetoclax dose to 100 mg once a day (if you've already completed the dose increment and are on a steady daily dose).

Dosage adjustment of Venclexta for moderate CYP3A inhibitors and P-GP inhibitors:

• Reduce venetoclax dose by at least half.
• After discontinuation of the inhibitor for 2-3 days, resume the previous venetoclax dose that was used before starting the inhibitor.

Dosage in the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma:

Dosage Considerations for Venetoclax in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma:

Posaconazole:

• Avoid using posaconazole at the start of venetoclax and during dose escalation.
• For patients already on a steady dose of venetoclax, consider using an alternative agent or decrease venetoclax dose to 70 mg/day if posaconazole must be used.

Strong CYP3A inhibitors (except posaconazole):

• Avoid using strong CYP3A inhibitors at the beginning of venetoclax and during dose escalation.
• For patients already on a steady dose of venetoclax, consider using an alternative agent or decrease venetoclax dose to 100 mg/day if a strong CYP3A inhibitor must be used.

Moderate CYP3A inhibitors and P-GP inhibitors:

• Consider using an alternative agent or decrease venetoclax dose by at least 50%.

Following discontinuation of CYP3A or P-gp inhibitors:

• After 2-3 days of discontinuing the inhibitor, restart venetoclax at the previous dose before starting the CYP3A or Pgp inhibitor.

Venetoclax Dose in Children

Efficacy and safety in children have not been established. 

Pregnancy Risk Category: C

• Venetoclax may cause harm to fetal health if given during pregnancy based on animal studies and mechanism of action.
• Women with reproductive potential should have a pregnancy test before starting treatment with venetoclax.
• Effective contraception should be used by women with reproductive potential for at least one month after the last dose of venetoclax.
• Venetoclax can cause male fertility problems.

Use of venetoclax while breastfeeding

• The presence of venetoclax in breast milk is unknown.
• The manufacturer does not recommend breastfeeding while taking venetoclax.

Venetoclax Dose in Renal Disease:

Dosage adjustment and monitoring based on renal function in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma:

Cockcroft-Gault Formula:

• To calculate CrCl in patients.
• Patients with altered renal function may require more intensive prophylaxis and monitoring to reduce the risk of tumor lysis syndrome after treatment initiation.

Creatinine Clearance (CrCl) ≥30 mL/minute:  

• No dosage adjustment is required; however, caution should be taken due to an increased risk for tumor lysis syndrome.
• Patients with altered renal function may require more intensive prophylaxis and monitoring to reduce the risk of tumor lysis syndrome after treatment initiation.

Creatinine Clearance (CrCl) <30 mL/minute:  

• The manufacturer of venetoclax does not recommend adjusting the dosage of the drug based on the patient's creatinine clearance (CrCl) if it is below 30 mL/minute, as there is not enough evidence to suggest that it is necessary.
• However, caution should still be taken in these patients as they may be at an increased risk for tumor lysis syndrome.

End-stage renal disease (ESRD) requiring dialysis:

• There are no dosage adjustments given in the manufacturer's labelling.
• Dialysis is unlikely to remove venetoclax significantly

Venetoclax Dose in Liver Disease:

• For patients with mild or moderate liver impairment (normal total bilirubin and AST > ULN or total bilirubin >1 to 1.5 × ULN), no dosage adjustment is required.
• For patients with severe liver impairment (total bilirubin >3 × ULN), no dosage adjustment is required.

Common Side Effects of Venetoclax (Venclexta) Include:

• Cardiovascular:
  • Edema
• Central Nervous System:
  • Fatigue
  • Headache
  • Dizziness
• Dermatologic:
  • Skin Rash
• Endocrine & Metabolic:
  • Hypocalcemia
  • Hyperglycemia
  • Hyperkalemia
  • Decreased Serum Albumin
  • Hypophosphatemia
  • Hyponatremia
  • Hyperphosphatemia
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Abdominal Pain
  • Constipation
  • Vomiting
  • Mucositis
• Hematologic & Oncologic:
  • Leukopenia
  • Neutropenia
  • Lymphocytopenia
  • Anemia
  • Thrombocytopenia
  • Tumor Lysis Syndrome
• Hepatic:
  • Increased Serum Aspartate Aminotransferase
• Neuromuscular & Skeletal:
  • Musculoskeletal Pain
  • Arthralgia
• Respiratory:
  • Upper Respiratory Tract Infection
  • Cough
  • Pneumonia
  • Dyspnea
  • Lower Respiratory Tract Infection
• Miscellaneous:
  • Fever

Less Common Side Effects of Venetoclax (Venclexta) Include:

• Endocrine & metabolic:
  • Hyperuricemia
• Hematologic & oncologic:
  • Febrile neutropenia

Contraindication to Venetoclax Include:

• Venetoclax is contraindicated in patients with a history of severe allergic reactions to venetoclax or any of its ingredients.
• For patients with CLL/SLL, it is not recommended to use strong CYP3A inhibitors during the ramp-up phase because it increases the risk of developing tumor lysis syndrome.

Warnings and precautions

Suppression of Bone Marrow:

• Anemia, thrombocytopenia and neutropenia can occur.
• In patients with CLL/SLL who have used venetoclax alone or in combination, grade 3 and 4 neutropenia are common.
• Monotherapy or combination therapy has been shown to reduce neutropenic fever.
• CBC and differential monitoring should be performed throughout treatment.
• You may need to interrupt treatment or reduce the dose.
• If clinically indicated, consider the use of antimicrobials or WBC growth factor support.
• Patients with AML will see their baseline neutrophil count drop if they are given azacitidine, decitabine or low-dose cytarabine.

Infection

• Venetoclax has been associated with fatal and serious infections, including pneumonia and sepsis.
• Be aware of any symptoms or signs of infection, such as fever, chills, cough, or difficulty breathing.
• If you experience grade 3 or higher infections, your doctor may recommend withholding venetoclax treatment.
• Seek medical attention immediately if you experience any symptoms or signs of infection.

Tumor lysis syndrome

• High tumor burden patients may develop tumor lysis syndrome, which can be fatal or cause kidney failure due to rapid tumor volume reduction by venetoclax.
• Patients with CLL/SLL have a higher risk of TLS and may have shorter ramp-up time and higher initial doses.
• TLS prophylaxis involves monitoring, ramp-up dose, and anti-hyperuricemic therapy such as allopurinol.
• Regular monitoring of blood chemistries is required, and prompt management is needed if any abnormality occurs.
• TLS risk increases with impaired renal function, high tumor burden, and use of strong or moderate CYP3A or P-gp inhibitors.
• Venetoclax dosage adjustment is required with any combination of strong or moderate CYP3A or P-gp inhibitors during ramp-up or after start-up.

Renal impairment

• Patients with reduced renal function, specifically CrCl < 80 mL/minute, may be at a greater risk of tumor lysis syndrome (TLS).
• These patients may require more intensive TLS prophylaxis and monitoring during treatment initiation and dose increase.
• It is important to regularly monitor blood chemistries and promptly treat any abnormalities.
• Treatment may need to be stopped or reduced if TLS risk increases.
• TLS risk could decline as the tumor burden drops.

Venetoclax: Drug Interaction

Monitor:

• During treatment with venetoclax, it is important to monitor CBC with differential counts, blood chemistries (including potassium, uric acid, and calcium), and assess tumor burden through radiographic evaluation such as a CT scan to evaluate for TLS.
• Females with reproductive potential should undergo a pregnancy test before treatment.
• Patients should be evaluated for their risk of TLS and monitored for signs and symptoms of infection.

Monitoring Blood Chemistry in Acute Myeloid Leukemia:

Before Therapy Initiation:

• Assess and treat pre-existing blood chemistry abnormalities.

Before the First Dose:

• Monitor blood chemistries for Tumour Lysis Syndrome (TLS).
• The next dose will be given 6-8 hours after the last dose.
• Patients at high risk of TLS need closer monitoring.

Monitoring Blood Chemistry based on Tumour Burden/Tumour Lysis Syndrome (TLS) Risk in Chronic Lymphocytic and/or Small Lymphocytic Leukemia:

Low Risk or Medium Risk (All Lymph Nodes <5cm and Absolute Lymphocyte Count [ALC] <25,000/mm):

• Check blood chemistry before the first dose, 6-8 hours after the first 20mg or 50mg dose, 24 hours after the 20mg or 50mg doses, and before each subsequent dose.

High Risk (Any Lymph Node >10cm or ALC >25,000/mm, and Any Lymph Node >5cm):

• Before the first dose, check blood chemistry 4, 8, 12, 24 and 24 hours following the first 20mg or 50mg dose.
• Check 6-8 hours after each subsequent initial ramp-up dose.

How to administer Venetoclax (Venclexta)?

Instructions for Taking Medication:

• Always take medication with a snack and a glass of water each day.
• Swallow the whole pill, without crushing or breaking it.

Missed or Vomited Doses:

• If you miss a dose, and it is within 8 hours of the missed time, take the missed dose as soon as possible and then resume your normal daily routine.
• If more than 8 hours have passed, do not take the missed dose. Instead, resume your normal dosing schedule the next day.
• If a patient vomits after receiving a dose, do not give an additional dose. Instead, administer the next prescribed dose at the normal time.

Mechanism of action of Venetoclax (Venclexta):

• Venetoclax is a drug that targets and kills cancer cells that have high levels of a protein called BCL-2.
• BCL-2 is important for cancer cells to survive and can make them resistant to chemotherapy.
• Venetoclax works by binding directly to the BCL-2 protein and replacing other proteins that would normally trigger cell death.
• This helps restore the natural process of cell death and can slow or stop the growth of cancer cells.

International Brands of Venetoclax:

• Venclexta
• Venclyxto
• Venclexta Starting Pack

Venetoclax Brands in Pakistan:

Not available.