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Acalabrutinib is indicated for:

1. Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)
• For the treatment of adult patients with CLL or SLL.
2. Mantle Cell Lymphoma (MCL)
• For the treatment of adult patients with mantle cell lymphoma who have received at least one prior therapy.
  [This indication is approved under accelerated approval based on the overall response rate. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.]

• The recommended dose of Acalabrutinib is 100 mg orally twice daily, approximately every 12 hours.
• Swallow capsules whole with water; do not open, chew, or crush the capsules.
• Acalabrutinib may be taken with or without food.
• Administer at the same times each day to maintain consistent drug levels.

Missed Dose Instructions:

• If a dose is missed by less than 3 hours, take it as soon as possible and continue with the regular dosing schedule.
• If missed by more than 3 hours, skip the missed dose and take the next dose at the usual time. Do not take extra doses to make up for a missed one.

Concomitant Use with Acid-Reducing Agents:

• Avoid use with proton pump inhibitors (e.g., omeprazole), as they may reduce drug absorption.
• If using an H2-receptor antagonist (e.g., famotidine), take Acalabrutinib at least 2 hours before the H2-blocker.
• If using antacids, take Acalabrutinib at least 2 hours before or after the antacid.

Acalabrutinib is a selective and covalent inhibitor of Bruton’s tyrosine kinase (BTK), a critical enzyme in the B-cell receptor (BCR) signaling pathway.

BTK plays a vital role in the activation, proliferation, and survival of malignant B cells. By irreversibly binding to the cysteine-481 residue of BTK, Acalabrutinib inhibits its activity, leading to disruption of downstream signaling pathways such as NF-κB, MAPK, and AKT.

This inhibition results in:

• Reduced survival of malignant B cells
• Impaired migration and adhesion of B cell

• Absorption:
  Acalabrutinib is rapidly absorbed after oral administration, with peak plasma concentrations typically reached within 0.5 to 2 hours. Food has minimal impact on the extent of absorption.
• Distribution:
  It is moderately bound to plasma proteins (~97.5%) and widely distributed throughout the body.
• Metabolism:
  Acalabrutinib is primarily metabolized in the liver by cytochrome P450 3A (CYP3A) enzymes. It is converted into its major active metabolite, ACP-5862, which retains pharmacologic activity.
• Elimination:
  Excreted mainly via the feces, with minimal renal elimination. Approximately 84% of the administered dose is recovered in feces and 12% in urine.
• Half-life:
  The terminal elimination half-life is approximately 1 to 2 hours, but the covalent binding to BTK leads to sustained pharmacodynamic effects despite a short plasma half-life.

Acalabrutinib is primarily metabolized by cytochrome P450 3A (CYP3A). Its plasma concentration can be significantly affected by drugs that influence CYP3A activity. Additionally, Acalabrutinib may increase the risk of bleeding when combined with antithrombotic agents.

🔺 CYP3A Inhibitors

Effect: ↑ Increased Acalabrutinib levels
Co-administration with strong or moderate CYP3A inhibitors can significantly increase Acalabrutinib exposure, which may enhance the risk of adverse effects.

• Examples:
• Strong inhibitors: Ketoconazole, Itraconazole, Clarithromycin, Ritonavir
• Moderate inhibitors: Fluconazole, Erythromycin, Verapamil
• Recommendation:
• Avoid strong inhibitors where possible.
• If unavoidable, monitor for toxicity and consider dose adjustment of Acalabrutinib.

🔻 CYP3A Inducers

Effect: ↓ Decreased Acalabrutinib levels
Strong CYP3A inducers can reduce Acalabrutinib plasma concentrations, potentially compromising its therapeutic effect.

• Examples: Rifampin, Phenytoin, Carbamazepine, St. John’s Wort
• Recommendation:
• Avoid use with strong inducers.
• If concurrent use is necessary, monitor efficacy and consider alternative agents if available.

⚠️ Antithrombotic Agents

Effect: ↑ Risk of bleeding
Acalabrutinib may increase bleeding risk when used with anticoagulants or antiplatelet agents.

• Examples: Warfarin, Aspirin, Clopidogrel, NSAIDs, Direct Oral Anticoagulants (DOACs)
• Recommendation:
• Use with caution.
• Monitor for signs of bleeding, especially in patients requiring dual therapy.

⚠️ Acid-Reducing Agents

Effect: ↓ Acalabrutinib absorption
Drugs that reduce stomach acidity may impair the solubility and absorption of Acalabrutinib.

• Proton Pump Inhibitors (PPIs): Avoid co-administration (e.g., Omeprazole, Esomeprazole)
• H2-Receptor Antagonists: Administer Acalabrutinib at least 2 hours before the H2-blocker
• Antacids: Administer Acalabrutinib at least 2 hours before or after antacids

✅ General Guidance

• Always review concomitant medications before initiating Acalabrutinib.
• Consider alternative agents if interaction risk is high.
• Monitor clinical response and adverse events closely when adding or removing interacting drugs.

Acalabrutinib commonly causes side effects such as headache, diarrhea, fatigue, nausea, muscle pain, bruising, and upper respiratory tract infections. Serious adverse effects may include bleeding (including gastrointestinal or intracranial hemorrhage), infections like pneumonia or sepsis, atrial fibrillation or flutter, low blood counts (neutropenia, anemia, thrombocytopenia), and secondary cancers such as skin malignancies. Patients should seek immediate medical attention if they experience high fever, severe bleeding, chest pain, palpitations, or signs of an allergic reaction.

Acalabrutinib is classified as Pregnancy Category D, meaning it may cause harm to a developing fetus and should not be used during pregnancy unless the benefits outweigh the risks. It is unknown whether Acalabrutinib is excreted in breast milk, so breastfeeding is not recommended during treatment. Women of childbearing potential should use effective contraception during treatment and for at least one week after the final dose, and men with female partners of reproductive potential should also use contraception during treatment and for at least one week after the last dose.

Tyrosine Kinase Inhibitor

• Hepatic Impairment:
  Acalabrutinib should be used with caution in patients with moderate hepatic impairment (Child-Pugh Class B). Severe hepatic impairment (Child-Pugh Class C) is a contraindication.
• Renal Impairment:
  No dose adjustment is necessary for patients with mild to moderate renal impairment. Safety and efficacy have not been established in patients with severe renal impairment.
• Geriatric Use:
  Clinical studies have not demonstrated significant differences in safety or efficacy between elderly patients (aged 65 years and older) and younger patients. However, caution is advised due to the increased likelihood of coexisting conditions and potential drug interactions.

Store Acalabrutinib at room temperature (20°C to 25°C or 68°F to 77°F) in its original container, protected from moisture and light. Keep out of reach of children and dispose of unused medication properly.