Acalabrutinib is a highly selective, potent small-molecule Bruton’s tyrosine kinase (BTK) inhibitor that prevents B-cell activation and signaling.
|Effects with food||
Food is unlikely to have clinically important effects.
Administration with acidic beverages, such as orange juice and grapefruit juice, decreased AUC by 40% and 17%, respectively.
|Peak plasma levels||
Median peak concentrations were reached after 0.9 hours, and 1.6 hours for the active metabolite, ACP-5862.
97.5% (acalabrutinib) and 98.6% (ACP-5862)
|Cross blood brain barrier?||
Acalabrutinib is primarily metabolized by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis.
84% (<2% as unchanged drug)
12% (<2% as unchanged drug)
terminal: 1 hr (acalabrutinib); 3.5 hrs (ACP-5862)
In combination with obinutuzumab or as monotherapy for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).
As monotherapy for the treatment of patients with CLL who have received at least one prior therapy.
For the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
The following adverse effects were reported in ≥ 5% of patients in a Phase III study of previously untreated CLL patients. It also includes severe, life-threatening and post-marketing adverse effects from other sources.
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Cardiovascular||Arrhythmia (4%) (may be severe)||E|
|Nausea, vomiting (22%) (generally mild)||E|
|General||Edema (9%) (peripheral)||E|
|Hematological||Hemorrhage (39%) (2% severe)||E|
|Myelosuppression (16%) (may be severe)||E|
|Hepatobiliary||↑ LFTs (20%)||E|
|Infection||Infection (65%) (may be severe)||E|
|Metabolic / Endocrine||Hyperuricemia (22%)||E|
|Tumor lysis syndrome (1%) (CLL)||I|
|Musculoskeletal||Musculoskeletal pain (32%)||E|
|Neoplastic||Secondary malignancy (8%) (6% non-melanoma skin)||D L|
|Nervous System||Dizziness (12%)||E|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for acalabrutinib include infection, bleeding, headache, diarrhea, musculoskeletal pain, hyperuricemia, nausea, vomiting, ↑ LFTs, rash and fatigue.
Atrial fibrillation or atrial flutter were reported in 4% of patients, including Grade 3 events in 1% of patients. Patients with severe cardiovascular disease were excluded from clinical trials.
Second primary malignancies, including skin and other solid tumours, have been reported. The most frequent was non-melanoma skin cancer (6%).
Grade 3 or 4 myelosuppression, including neutropenia, anemia, and thrombocytopenia have occurred during treatment, and should be monitored.
A temporary increase in lymphocyte counts (≥50% from baseline and a post baseline assessment ALC ≥5 x 109 /L) has occurred in 54% of patients, upon initiation of treatment. The median time to onset and duration of lymphocytosis were 1 week and 7 weeks, respectively.
Serious hemorrhagic events have occurred in patients with (4%) and without (3%) concomitant antithrombotic agents. Patients who were receiving warfarin or other vitamin K antagonists or who had a recent history of stroke or intracranial hemorrhage were excluded from clinical trials.
Serious infections, including fatal, have been reported. Pneumonia was the most frequent. Progressive multifocal leukoencephalopathy (PML) and infections due to hepatitis B virus (HBV) reactivation have been reported. Opportunistic infections, such as aspergillosis, fungal pneumonia, and Pneumocystis Jiroveci Pneumonia (PJP), have also occurred.
Refer to protocol by which the patient is being treated.
Acalabrutinib is affected by CYP3A inducers and inhibitors; see Drug Interaction section for dose adjustments.
Consider the benefit-risk analysis of withholding acalabrutinib for at least 3 days pre-and post-surgery due to bleeding risk.
Consider prophylaxis for tumour lysis syndrome (TLS) in patients at higher risk of TLS (ex. first cycle in patients with CLL)
Consider prophylaxis in patients at increased risk for opportunistic infections (e.g. aspergillosis, fungal pneumonia, and Pneumocystis Jiroveci Pneumonia).
|Dose level||Acalabrutinib dose|
|0||100 mg BID|
|-1||100 mg Daily|
Grade ≥ 3 non-hematologic toxicities
Grade 3 thrombocytopenia with significant bleeding
Grade 4 thrombocytopenia
Grade 4 neutropenia lasting longer than 7 days
|First and second||
Hold until toxicity is Grade 1 or baseline.
Resume at same dose.
Hold until toxicity is Grade 1 or baseline.
Resume at 1 dose level ↓.
|Hepatic impairment||Total bilirubin||AST||Acalabrutinib dose|
Mild or Moderate (Child-Pugh A or B)
|≤ 3 X ULN||Any||No dose adjustment required.|
|Severe (Child-Pugh C)||> 3 X ULN||Any||Avoid use.|
|Approximate creatinine clearance* (mL/min)||Acalabrutinib dose|
|≥ 30||No dose adjustment required.|
|< 30||No data available.|
*Reported as eGFR in mL/min/1.73m2, as estimated by MDRD.
No dose adjustment is necessary due to age. Clinically relevant differences in safety or efficacy were not observed between those ≥ 65 years and < 65 years.
Safety and efficacy in children have not been established.
- Administer acalabrutinib with or without food.
- Capsules should be swallowed whole with a glass of water. Do not crush, dissolve or open capsules. Acidic beverages (i.e. orange juice or grapefruit juice) decrease absorption of acalabrutinib.
- If a dose is missed, patient may take within 3 hours of missed dose. If more than 3 hours, the dose should be skipped and taken at the next planned time. Extra capsules should not be taken to make up for missed dose.
- Grapefruit, starfruit, Seville oranges, their juices or products should be avoided during acalabrutinib treatment.
- Store at room temperature, in original bottle, and away from children or pets.
- Patients who are hypersensitive to acalabrutinib or to any ingredient in the formulation or component of the container.
- Avoid in patients with severe hepatic impairment (Child-Pugh C or total bilirubin > 3 times ULN, regardless of AST levels).
- Avoid concomitant use of strong CYP3A4 inhibitors.
- Use caution in patients at risk of bleeding, including those receiving concomitant antiplatelet or anticoagulant medications. Consider the benefits and risks of withholding acalabrutinib for at least 3 days pre-and post-surgery.
- Use caution in patients at risk of cardiac arrhythmias (e.g. history of atrial fibrillation or infection / pneumonia).
- Use caution when driving or operating a vehicle or potentially dangerous machinery due to fatigue and dizziness.
Documented in animals
Acalabrutinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months (general recommendation) after the last dose.
Excretion into breast milk:
Breastfeeding is not recommended during treatment and for 2 weeks after receiving the last dose.
No data on the effect of acalabrutinib on human fertility. No effects on fertility were observed in animals exposed up to 10 times the human AUC at the recommended dose.
Acalabrutinib is primarily metabolized by CYP3A enzymes. No interaction is expected with CYP3A substrates.
Acalabrutinib may increase exposure to BCRP substrates (e.g. methotrexate) by intestinal BCRP inhibition; ACP-5862 (active metabolite) may increase exposure to MATE1 substrates by MATE1 inhibition.
Administration with acidic beverages (i.e. orange juice or grapefruit juice) decreases absorption of acalabrutinib.
|CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit)||↑ acalabrutinib concentration and/or toxicity||↓ metabolism of acalabrutinib||Avoid. If co-administration with a strong CYP3A inhibitor is short-term, hold acalabrutinib. When co-administered with a moderate CYP3A inhibitor, ↓ dose to 100 mg daily.|
|Strong CYP3A4 inducers (i.e. phenytoin, rifampin, carbamazepine, etc)||↓ acalabrutinib concentration and/or efficacy||↑ metabolism of acalabrutinib||Avoid.|
|Gastric acid reducing agents (i.e. proton pump inhibitors, H2-receptor antagonists, antacids)||↓ acalabrutinib concentration and/or efficacy||↓ acalabrutinib absorption||Avoid use with proton pump inhibitors. Take acalabrutinib 2 hours before taking a H2-receptor antagonist. Separate dosing by at least 2 hours with antacids.|
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
|Baseline and at each visit|
Renal and liver function tests
|Baseline and at each visit|
|Baseline and as clinically indicated|
Clinical toxicity assessment for cardiac symptoms, skin cancers, infection, hyperuricemia, TLS, GI effects, pain and bleeding
|At each visit|
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Acalabrutinib: DynaMed drug monograph. Dec 06, 2019.
Acalabrutinib: UpToDate® drug information (v48.0). Accessed Jan 30, 2020.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Antiemesis: Version 1.2019, 2019.
Product Monograph: Calquence (acalabrutinib). AstraZeneca Canada Inc. Nov 28, 2019.
Sharman JP, Banerji V, Fogliatto LM, et al. Elevate TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naïve chronic lymphocytic leukemia. Blood 2019; 134 (Supplement_1): 31.https://doi.org/10.1182/blood-2019-128404.
January 2021 Updated administration section
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