Ibruxen

Ibrutinib is approved for the treatment of various B-cell malignancies and related disorders:

• Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL): Used as first-line therapy and for relapsed or refractory cases, including patients with 17p deletion or TP53 mutation.
• Mantle Cell Lymphoma (MCL): For patients with relapsed or refractory disease after at least one prior therapy.
• Waldenström’s Macroglobulinemia (WM): For patients requiring therapy, including those with relapsed or refractory disease.
• Marginal Zone Lymphoma (MZL): For patients who have received at least one prior anti-CD20-based therapy.
• Chronic Graft-versus-Host Disease (cGVHD): For patients who have failed one or more systemic therapies.

Off-label uses:
Ibrutinib is sometimes used in other B-cell malignancies under clinical investigation or specialist discretion.

Adults:

• CLL/SLL: 420 mg orally once daily continuously.
• Mantle Cell Lymphoma: 560 mg orally once daily continuously.
• Waldenström’s Macroglobulinemia: 420 mg orally once daily.
• Marginal Zone Lymphoma: 560 mg orally once daily.
• Chronic Graft-versus-Host Disease: 420 mg orally once daily.

Pediatrics:
Safety and efficacy not established; use only in clinical trials.

Elderly:
No dose adjustment solely for age; monitor for tolerability.

Renal Impairment:
No adjustment needed for mild to moderate impairment. Caution with severe impairment due to limited data.

Hepatic Impairment:

• Mild (Child-Pugh A): No adjustment required.
• Moderate to severe (Child-Pugh B or C): Avoid use or reduce dose to 140 mg once daily if benefit outweighs risk.

Administration:

• Swallow capsules whole with water.
• Can be taken with or without food.
• Avoid grapefruit juice and other strong CYP3A4 inhibitors.

Duration:
Treatment continues until disease progression or unacceptable toxicity occurs.

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK), a crucial enzyme in B-cell receptor signaling. By covalently binding to the cysteine-481 residue of BTK, it blocks downstream signaling pathways that promote malignant B-cell proliferation, survival, adhesion, and migration. This inhibition leads to apoptosis of malignant B cells and reduces disease progression in B-cell malignancies.

• Absorption: Rapid, with peak plasma concentration in 1–2 hours.
• Bioavailability: Approximately 60%.
• Distribution: Highly protein-bound (~97%).
• Metabolism: Primarily metabolized by hepatic CYP3A4; minor contribution from CYP2D6.
• Active Metabolites: Major metabolite PCI-45227 has approximately 15% of the activity of the parent drug.
• Half-life: Effective half-life 4–6 hours, but sustained pharmacodynamic effect due to irreversible BTK binding.
• Excretion: Mainly via feces (~80%) and urine (~10%).

• Pregnancy: FDA Pregnancy Category D. Animal studies show fetal harm; human data limited. Use only if benefits outweigh risks.
• Lactation: Unknown if excreted in human milk. Breastfeeding not recommended during treatment and for at least 1 month after the last dose due to potential risks to the infant.
• Contraception: Women of childbearing potential should use effective contraception during treatment and for one month afterward.

• Primary Class: Bruton's Tyrosine Kinase (BTK) Inhibitor
• Subclass: Targeted small molecule kinase inhibitor

• Known hypersensitivity to Ibrutinib or any formulation components.
• Concurrent use of strong CYP3A4 inhibitors or inducers without appropriate dose adjustments.
• Severe hepatic impairment without appropriate dose modification.
• Pregnancy unless benefits clearly outweigh risks.

• Bleeding: Increased risk of major and minor bleeding events. Use caution with anticoagulants and antiplatelet drugs. Monitor for signs of bleeding.
• Infections: Increased risk, including opportunistic infections. Prompt evaluation and treatment of infections recommended.
• Cardiac Arrhythmias: Atrial fibrillation and other arrhythmias reported; monitor closely, especially in patients with cardiac history.
• Hypertension: New or worsening hypertension may occur; monitor and manage accordingly.
• Cytopenias: Monitor blood counts regularly due to risk of neutropenia, anemia, and thrombocytopenia.
• Tumor Lysis Syndrome: Monitor and take preventive measures in patients with high tumor burden.
• Secondary Malignancies: Increased risk of skin cancers and other malignancies; recommend regular dermatologic exams and sun protection.

Common Adverse Effects:

• Hematologic: neutropenia, thrombocytopenia, anemia.
• Gastrointestinal: diarrhea, nausea, vomiting, abdominal pain.
• Fatigue.
• Musculoskeletal pain and arthralgia.
• Upper respiratory infections.
• Rash.
• Peripheral edema.

Serious but Rare:

• Major bleeding events (including gastrointestinal and intracranial hemorrhage).
• Atrial fibrillation and other cardiac arrhythmias.
• Severe infections, including pneumonia.
• Tumor lysis syndrome.
• Secondary malignancies (including skin cancer).

• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Increase Ibrutinib plasma concentration; may increase toxicity. Dose adjustment or avoidance recommended.
• CYP3A4 inducers (e.g., rifampin, carbamazepine): Decrease Ibrutinib levels; may reduce efficacy. Avoid concomitant use.
• Anticoagulants and antiplatelets: Increase bleeding risk; monitor closely.
• Grapefruit and Seville oranges: Inhibit CYP3A4; avoid consumption during treatment.
• P-glycoprotein substrates: Potential interaction; caution advised.

• Clinical guidelines increasingly recommend Ibrutinib as first-line therapy for CLL, including patients with high-risk genetic mutations.
• FDA and EMA have issued updated warnings about bleeding and cardiac arrhythmias, emphasizing monitoring.
• Expanded indication approval for Marginal Zone Lymphoma.
• New dosing recommendations for patients with hepatic impairment.
• Research ongoing on combination regimens and next-generation BTK inhibitors aiming to improve safety and efficacy.

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F).
• Protect from moisture and light.
• Keep capsules in the original container until use.
• Do not freeze.
• Keep out of reach of children.