ACALABRUTINIB
Clinical safety rating
cautionComprehensive clinical and safety monograph for ACALABRUTINIB (ACALABRUTINIB).
Comprehensive clinical and safety monograph for ACALABRUTINIB (ACALABRUTINIB).
Treatment of adult patients with mantle cell lymphoma who have received at least one prior therapyTreatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma
Acalabrutinib is a selective, irreversible inhibitor of Bruton tyrosine kinase. It forms a covalent bond with a cysteine residue in the active site, blocking B-cell receptor signaling and inhibiting malignant B-cell proliferation and survival.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP2C8 and glutathione conjugation. |
| Excretion | Primarily hepatic metabolism (CYP3A4); fecal excretion accounts for approximately 86% (including 69% as metabolites, 17% as unchanged drug). Renal excretion is minimal (<1% unchanged). |
| Half-life | Terminal elimination half-life is approximately 1 hour. Clinical context: short half-life supports twice-daily dosing, but BTK occupancy remains >90% over 12 hours due to irreversible binding. |
| Protein binding | 97% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 34 L (approx. 0.5 L/kg for a 70 kg adult), indicating moderate distribution into tissues. |
| Bioavailability | Oral bioavailability: approximately 70–75% (absolute bioavailability not determined in humans; estimate based on mass balance and exposure data). |
| Onset of Action | Oral: maximal BTK occupancy occurs within 8 hours after a single dose; clinical response (e.g., lymphocytosis reduction in CLL) typically observed within 1–2 weeks. |
| Duration of Action | Pharmacodynamic duration (BTK occupancy) persists for >12 hours; clinical duration of effect is continuous with daily dosing; disease progression may occur if therapy interrupted. |
| Molecular Weight | 465.5 |
100 mg orally every 12 hours.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for CrCl ≥30 mL/min. For CrCl <30 mL/min, reduce dose to 100 mg orally once daily. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 100 mg orally once daily. Child-Pugh C: Avoid use. |
| Pediatric use | Not approved for patients <18 years; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment; monitor for toxicity, especially infections and bleeding. |
| 1st trimester | Avoid. Acalabrutinib is a BTK inhibitor with potential teratogenic effects based on animal studies; there are no adequate human studies. |
| 2nd trimester | Avoid. May cause fetal harm; no human data available. |
| 3rd trimester | Avoid. Potential risk of fetal toxicity and impaired immune development. |
Clinical note
Comprehensive clinical and safety monograph for ACALABRUTINIB (ACALABRUTINIB).
| Placental transfer | Likely crosses placenta based on molecular weight and animal studies showing fetal exposure. |
| Breastfeeding | No data on presence in human milk. Because of potential for serious adverse reactions including immunosuppression, advise women not to breastfeed during treatment and for at least 2 weeks after last dose. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | Acalabrutinib is a BTK inhibitor. Animal studies show embryo-fetal toxicity including malformations and reduced fetal weight at maternal exposures below clinical doses. In humans, no adequate data; however, based on mechanism and animal findings, there is potential risk of teratogenicity, especially during first trimester. Use during pregnancy should be avoided unless maternal benefit outweighs fetal risk. |
| Fetal Monitoring | If used during pregnancy, monitor for maternal hematologic toxicity (neutropenia, thrombocytopenia) and infection. Fetal monitoring should include ultrasound for growth restriction and anomalies. Liver function tests and complete blood counts should be obtained periodically. |
| Fertility Effects | No formal studies on fertility in humans. In animal studies, no effects on male or female fertility were observed at clinically relevant doses. However, BTK inhibitors may impact ovarian function based on mechanism; consider fertility preservation counseling for patients of reproductive potential. |
■ FDA Black Box Warning
No boxed warning is included in the FDA-approved prescribing information.
| Serious Effects |
Hypersensitivity to acalabrutinib or any excipients
| Precautions | Hemorrhage: Fatal bleeding events have occurred; monitor for bleeding and manage appropriately, Infections: Serious infections (including opportunistic infections) have occurred; consider prophylaxis, Cytopenias: Grade 3/4 neutropenia, thrombocytopenia, and anemia; monitor blood counts, Second primary malignancies: Including skin cancers; advise sun protection, Atrial fibrillation and flutter: Monitor for cardiac arrhythmias, Hepatotoxicity: Elevations of liver enzymes; monitor hepatic function |
| Food/Dietary | Avoid grapefruit, grapefruit juice, and Seville oranges due to CYP3A4 inhibition increasing acalabrutinib exposure. No other significant food interactions. |
| Clinical Pearls | Monitor for bleeding, especially if on antiplatelet or anticoagulant therapy. Acalabrutinib is a selective BTK inhibitor with minimal off-target effects compared to ibrutinib, but still carries risks of atrial fibrillation, hypertension, and infections. Start with 100 mg twice daily until progression or unacceptable toxicity. Administer with a full glass of water; do not open capsules. Consider dose reduction for severe hepatic impairment (Child-Pugh C). |
| Patient Advice | Take exactly as prescribed, twice daily about 12 hours apart. · Swallow capsules whole with water; do not crush or chew. · Avoid grapefruit, grapefruit juice, and Seville oranges during treatment. · Report any signs of bleeding (unusual bruising, black/tarry stools, blood in urine) or infection (fever, chills) immediately. · Use effective contraception during treatment and for at least 1 week after last dose. · Do not stop or change dose without consulting your doctor. · Wash hands frequently and avoid crowds to reduce infection risk. |
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