Generic Name

Brukinsa

Mechanism

• Irreversible covalent inhibition of BTK at Cys‑481, blocking B‑cell receptor signaling.
• Leads to apoptosis, impaired migration, and decreased proliferation of malignant B‑cells.
• Also exhibits off‑target inhibition of EGFR, VEGFR, ITK, and TEC family kinases, contributing to efficacy and toxicity.

Pharmacokinetics

• Route: Oral; food reduces AUC by ~30 %.
• Absorption: ~100 % oral bioavailability.
• Distribution: high protein binding (~97 %).
• Metabolism: Predominantly CYP3A4/3A5 → active metabolites.
• Elimination: ~70 % in feces, 30 % in urine.
• Half‑life: 4–8 h (steady‑state achieved by day 3).
• Drug interactions: Contraindicated with strong CYP3A4 inducers (e.g., rifampin) or inhibitors (e.g., ketoconazole) that may alter systemic exposure.

Indications

• Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) – first‑line monotherapy or with obinutuzumab.
• Waldenström macroglobulinemia – monotherapy or in combination.
• Mantle cell lymphoma (MCL) – relapsed/refractory or as part of a combination.
• *Label includes use in other B‑cell malignancies under specific approvals.*

Contraindications

• Severe hepatic impairment (Child‑Pugh C).
• Pregnancy/Breastfeeding (category X; teratogenic in animal models).
• Known hypersensitivity to ibrutinib or any excipients.
• Active bleeding or uncontrolled hypertension – increased risk for hemorrhage and cardiovascular events.

Warnings
• Bleeding: increased risk with anticoagulants, antiplatelet agents, NSAIDs, and aspirin.
• Infections: opportunistic infections (Pneumocystis jiroveci, HSV, varicella zoster).
• Cardiovascular: atrial fibrillation, ventricular arrhythmias, hypertension.
• Cytopenias: neutropenia, thrombocytopenia, anemia.

Dosing

• Standard dose: 420 mg orally once daily (single 420 mg tablet).
• Loading dose: none; start at maintenance dose.
• With food: may reduce bioavailability – patients advised to take on an empty stomach or standardize meal timing.
• Concomitant drugs: avoid strong CYP3A4 inhibitors/inducers.

Adverse Effects

Common (≥10 %)
• Diarrhea, nausea, vomiting.
• Fatigue, mild myalgias.
• Skin rash (maculopapular).

Serious (≥1 %)
• Bleeding: epistaxis, gastrointestinal hemorrhage, intracranial bleed.
• Infections: PCP pneumonia, herpes zoster (dose‑adjustable).
• Cardiac: arrhythmias (especially atrial fibrillation), hypertension, cardiac ischemia.
• Cytopenias: thrombocytopenia (≥50 %), neutropenia.

Monitoring

Clinical Pearls

• Dose adjustment for hepatic impairment: Reduce to 280 mg daily in Child‑Pugh B; contraindicated in Child‑Pugh C.
• Drug‑drug interactions: Ketoconazole or ritonavir can elevate levels up to 10×, necessitating dose reduction or avoidance.
• Prophylaxis: Initiate TMP‑SMX prophylaxis for PCP if neutropenia 1 mg/kg/day.
• Anticoagulation caution: In patients with atrial fibrillation on warfarin, consider direct oral anticoagulants (DOACs) but monitor INR closely; dose adjustments may be required.
• Pain management: Avoid NSAIDs due to bleeding risk; use acetaminophen or low‑dose opioids if needed.
• Patient adherence: Emphasize strict no‑skip scheduling since ibrutinib’s half‑life is relatively short; missed doses can lead to sub‑therapeutic BTK inhibition and disease progression.

Key Takeaway: Brukinsa’s potent BTK inhibition renders it a cornerstone for CLL and other B‑cell malignancies, but its efficacy is counterbalanced by notable bleeding, cardiovascular, and infectious risks that require vigilant monitoring and drug‑interaction management.