Venetoclax Drug

Indications

Venetoclax is a medication used in the treatment of certain types of cancer, particularly chronic lymphocytic leukemia (CLL), small  lymphocytic leukemia (SLL) and acute myeloid leukemia (AML).

 

Venetoclax has been shown to be effective in treating CLL, both as a single agent and in combination with other drugs. It has also shown promise in the treatment of AML, particularly in combination with other chemotherapy agents.

 

Venetoclax FDA Approval

In 2015, the United States Food and Drug Administration (FDA) acknowledged the breakthrough potential of venetoclax for individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had relapsed, developed intolerance to, or were refractory to previous treatments.

Subsequently, in December 2016, venetoclax received approval for use in the European Union. 

 

Clinical Trial

Venetoclax drug’s efficacy was established through a single-arm clinical trial involving 106 participants with CLL and a 17p deletion who had undergone at least one prior therapy. 

 

Administered orally, venetoclax doses escalated from 20 mg to 400 mg over five weeks. The trial, spanning multiple countries including the US, Canada, France, Germany, Poland, the United Kingdom, and Australia, demonstrated that 80% of participants experienced either complete or partial cancer remission.

 

By June 2018, the FDA granted regular approval for venetoclax in CLL or SLL patients, regardless of 17p deletion status, who had undergone at least one prior therapy. 

 

Then, in November 2018, the FDA approved venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults aged 75 years or older, or those with comorbidities precluding intensive induction chemotherapy in the United States.

 

Mechanism of Action

Venetoclax is a medication used to treat certain types of cancer by targeting a specific protein in cancer cells.

Understanding Cancer Cell Survival: Cancer cells, like all cells, have a natural process called apoptosis, which is a way for cells to die when they are damaged or no longer needed. However, cancer cells often avoid this process, allowing them to survive and grow uncontrollably.

 

Role of BCL-2 Protein: A protein called BCL-2 helps cancer cells avoid apoptosis. Think of BCL-2 as a shield that protects cancer cells from dying. In many cancers, especially certain types of leukemia, the BCL-2 protein is overactive, making it very hard for these cells to die.

 

How Venetoclax Works: Venetoclax is designed to specifically target and bind to the BCL-2 protein. By binding to BCL-2, venetoclax effectively takes away the shield that protects cancer cells.

 

Restoring Apoptosis: Without the protective shield of BCL-2, the cancer cells can no longer avoid apoptosis. This means they are more likely to die off naturally, which helps to reduce the number of cancer cells in the body.

 

In summary, venetoclax works by targeting and inhibiting the BCL-2 protein, removing the protection it gives to cancer cells, and allowing these cells to undergo apoptosis and die. This helps to control and reduce cancer.

 

Venetoclax Side Effects

Common Side Effects

• Neutropenia: A significant decrease in neutrophils, a type of white blood cell essential for fighting infections.
• Anemia: Low red blood cell count, leading to fatigue and weakness.
• Thrombocytopenia: Low platelet count, which can increase the risk of bleeding and bruising.
• Gastrointestinal Issues: Nausea, Diarrhea, Vomiting, Constipation

• Fatigue: General tiredness and lack of energy.
• Upper Respiratory Tract Infection: Increased susceptibility to infections like the common cold.
• Fever: Elevated body temperature, often as a response to infection.
• Musculoskeletal Pain: Pain in muscles, bones, or joints.

 

Serious Side Effects

Tumor Lysis Syndrome (TLS): This is a potentially life-threatening condition caused by the rapid death of cancer cells, leading to the release of their contents into the bloodstream. Symptoms can include nausea, vomiting, diarrhea, muscle cramps, and renal failure. Prophylactic measures, including hydration and medications, are often employed to prevent TLS when starting venetoclax.

Severe Neutropenia: This can lead to serious infections, sometimes requiring hospitalization and treatment with antibiotics.

Severe Anemia and Thrombocytopenia: These can necessitate blood transfusions and other supportive care measures.

Infections: Increased risk of serious bacterial, viral, or fungal infections due to immunosuppression.

Electrolyte Imbalances: Including hyperkalemia (high potassium levels), hyperphosphatemia (high phosphate levels), hypocalcemia (low calcium levels), and hyperuricemia (high uric acid levels).

 

Dosage and Administration

Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)

For CLL/SLL, venetoclax is usually administered in combination with other medications, such as rituximab or obinutuzumab. The dosage involves a gradual ramp-up over several weeks to minimize the risk of tumor lysis syndrome (TLS).

Ramp-Up Dosing Schedule

• Week 1: 20 mg once daily
• Week 2: 50 mg once daily
• Week 3: 100 mg once daily
• Week 4: 200 mg once daily
• Week 5 and beyond: 400 mg once daily

 

Acute Myeloid Leukemia (AML)

For AML, venetoclax is typically used in combination with either azacitidine, decitabine, or low-dose cytarabine in patients who are 75 years or older or who have comorbidities that preclude the use of intensive induction chemotherapy.

Starting Dosage

• Days 1: 100 mg once daily
• Days 2: 200 mg once daily
• Days 3 and beyond: 400 mg once daily (if administered with azacitidine or decitabine) or 600 mg once daily (if administered with low-dose cytarabine)

 

Administration Guidelines

• With Food and Water: Venetoclax should be taken with a meal and water to enhance absorption and reduce gastrointestinal side effects.
• Swallow Whole: Do not crush, chew, or break the tablets.
• Missed Dose: If a dose is missed by less than 8 hours, it should be taken as soon as remembered. If more than 8 hours have passed, skip the missed dose and resume the usual dosing schedule the next day.

 

Venetoclax Drug Interactions

CYP3A Inhibitors and Inducers

Strong CYP3A Inhibitors

These drugs can significantly increase venetoclax plasma concentrations, raising the risk of toxicity, including tumor lysis syndrome (TLS). If co-administration cannot be avoided, dose adjustments are necessary.

• Examples: Ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, ritonavir, indinavir, lopinavir, saquinavir.
• Dose Adjustment: Venetoclax dose should be reduced by at least 75% when used with strong CYP3A inhibitors.

 

Moderate CYP3A Inhibitors

These can also increase venetoclax levels but to a lesser extent.

• Examples: Erythromycin, fluconazole, diltiazem, verapamil.
• Dose Adjustment: Venetoclax dose should be reduced by at least 50% when used with moderate CYP3A inhibitors.

 

Strong and Moderate CYP3A Inducers

These drugs can decrease venetoclax plasma concentrations, potentially reducing its effectiveness. Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort.

Dose Adjustment: Venetoclax is not recommended to be used with strong CYP3A inducers due to the risk of reduced efficacy.

 

Anticoagulants and Antiplatelet Agents

Venetoclax can increase the risk of bleeding, especially when taken with anticoagulants or antiplatelet agents. Examples: Warfarin, heparin, aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs (NSAIDs).

Management: Close monitoring for signs of bleeding and appropriate adjustments as necessary.

 

Other Notable Interactions

P-glycoprotein (P-gp) Inhibitors

Venetoclax is a substrate for P-gp, and inhibitors of this transporter can increase venetoclax levels. Examples: Cyclosporine, tacrolimus, amiodarone.

Management: Monitor for increased adverse reactions and adjust venetoclax dose if needed.

 

Gastric pH Modifiers

Drugs that alter gastric pH, such as proton pump inhibitors (PPIs) and H2 antagonists, may affect venetoclax absorption. Examples: Omeprazole, pantoprazole, ranitidine, famotidine.

Management: No specific dose adjustment is generally required, but close monitoring is advised.

 

Food and Grapefruit Juice

Grapefruit and Seville Oranges: These can inhibit CYP3A and increase venetoclax levels. Patients should avoid consuming grapefruit or Seville oranges while taking venetoclax.