Acaluxen

• FDA-Approved Uses:
• Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL):
• For the treatment of adult patients with CLL or SLL, both treatment-naïve and previously treated.
• Mantle Cell Lymphoma (MCL):
• For adult patients with MCL who have received at least one prior therapy (approved under accelerated approval based on response rate).
• Clinically Accepted Off-Label Uses:
• Waldenström’s Macroglobulinemia in patients intolerant to first-generation BTK inhibitors.
• Marginal Zone Lymphoma (MZL): under investigation; supported by emerging data.
• CNS-involved B-cell lymphomas: investigational; crosses blood-brain barrier.

• Standard Adult Dose:
• 100 mg orally every 12 hours until disease progression or unacceptable toxicity.
• Administration Instructions:
• May be taken with or without food.
• Swallow capsules whole with water; do not open, chew, or crush.
• Avoid proton pump inhibitors (PPIs); separate from H2-receptor antagonists by at least 2 hours.
• Dose Modifications:
• Hepatic Impairment:
• Mild to moderate (Child-Pugh A or B): Use with caution.
• Severe (Child-Pugh C): Not recommended.
• Renal Impairment:
• No dose adjustment necessary for mild to moderate impairment.
• Drug Interactions:
• With strong CYP3A inhibitors: Reduce to 100 mg once daily.
• Avoid strong CYP3A inducers.

Acalabrutinib is a second-generation Bruton’s tyrosine kinase (BTK) inhibitor. It binds covalently to cysteine-481 in the BTK active site, irreversibly inhibiting BTK, a key kinase in the B-cell receptor (BCR) signaling pathway. This inhibition disrupts downstream signaling, leading to decreased proliferation and survival of malignant B cells. Acalabrutinib is more selective than first-generation inhibitors, minimizing off-target effects on kinases such as EGFR, TEC, and ITK.

• Absorption:
• Rapid absorption; peak plasma concentration (Tmax): ~1 hour.
• Absolute bioavailability: ~25%.
• Gastric pH affects absorption; avoid PPIs.
• Distribution:
• Volume of distribution: ~98 L.
• Plasma protein binding: ~97.5%.
• Metabolism:
• Metabolized primarily by CYP3A4 to an active metabolite (ACP-5862), which is approximately half as potent.
• Excretion:
• Urine: ~84% (mostly as metabolites), feces: ~5%.
• Half-life: Parent drug ~1–2 hours; active metabolite ~6–9 hours.

• Pregnancy:
• Contraindicated; based on animal data, may cause fetal harm.
• Advise contraception during treatment and for at least 1 week after the last dose.
• Lactation:
• Unknown if excreted in human milk.
• Discontinue breastfeeding during treatment and for at least 2 weeks after the last dose.
• Contraception:
• Effective contraception is required for both males and females of reproductive potential.

• Primary Class: Antineoplastic Agent
• Subclass: Bruton’s Tyrosine Kinase (BTK) Inhibitor, Second-Generation

• Hypersensitivity to acalabrutinib or any component of the formulation.
• Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine).
• Severe hepatic impairment (Child-Pugh Class C).

• Hemorrhage: Risk of serious bleeding; caution with anticoagulants or antiplatelet agents.
• Infections: Risk of bacterial, viral (e.g., hepatitis B reactivation), and fungal infections; monitor and treat promptly.
• Cytopenias: Monitor complete blood counts regularly.
• Atrial Fibrillation/Flutter: Monitor patients with cardiac risk factors.
• Secondary Primary Malignancies: Skin cancers reported; advise sun protection.
• Tumor Lysis Syndrome (TLS): Risk in high tumor burden; monitor electrolytes.
• Gastric pH–Altering Agents: Avoid PPIs; separate dosing with H2-blockers and antacids.

• Common (≥10%):
• Hematologic: Neutropenia, thrombocytopenia, anemia.
• General: Headache, fatigue, bruising.
• GI: Diarrhea, nausea, constipation.
• Infectious: Upper respiratory tract infections, pneumonia.
• Skin: Rash.
• Serious/Rare:
• Major hemorrhage.
• Atrial fibrillation.
• Hepatitis B reactivation.
• Second primary malignancies (e.g., skin cancers).
• Onset & Management:
• Most adverse events occur early and are manageable with supportive care or dose adjustments.

• CYP3A4 Inhibitors (e.g., ketoconazole): Increase acalabrutinib exposure — reduce dose.
• CYP3A4 Inducers (e.g., rifampin): Decrease efficacy — avoid use.
• Proton Pump Inhibitors (e.g., omeprazole): Decrease absorption — contraindicated.
• Antiplatelets/Anticoagulants: Increased bleeding risk — use with caution.
• Metabolic Pathway:
• Primarily metabolized by CYP3A4.

• FDA Approval Updates:
• Full approval for CLL/SLL based on long-term survival and progression-free survival (PFS) data.
• NCCN Guidelines:
• Listed as a preferred first-line agent for CLL/SLL.
• Favorable safety profile compared to ibrutinib in patients with cardiac comorbidities.
• EMA Guidance:
• Approved for CLL and MCL under similar conditions as FDA.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Excursion Range: Allowable between 15°C and 30°C (59°F to 86°F).
• Handling:
• Store in original bottle with desiccant.
• Protect from moisture and light.
• Do not use if capsules are broken or damaged.