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A - Drug Name

acalabrutinib

COMMON TRADE NAME(S):   Calquence®

 
B - Mechanism of Action and Pharmacokinetics

Acalabrutinib is a highly selective, potent small-molecule Bruton’s tyrosine kinase (BTK) inhibitor that prevents B-cell activation and signaling.



Absorption
Bioavailability

25%

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.


Distribution
PPB

97.5% (acalabrutinib) and 98.6% (ACP-5862) 

Cross blood brain barrier?

Unknown

Metabolism

Acalabrutinib is primarily metabolized by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis.

Active metabolites

yes

Elimination
Feces

84% (<2% as unchanged drug)

Urine

12% (<2% as unchanged drug)

Half-life

terminal: 1 hr (acalabrutinib); 3.5 hrs (ACP-5862) 

 
C - Indications and Status
Health Canada Approvals:

  • 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.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

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
Dermatological Rash (19%) E
Gastrointestinal Constipation (11%) E
Diarrhea (35%) E
Nausea, vomiting (22%) (generally mild) E
General Edema (9%) (peripheral) E
Fatigue (18%) 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
Headache (37%) 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 intiation 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.

 
E - Dosing

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).



Adults:

Oral: 100 mg BID

Dosage with Toxicity:

Dose level Acalabrutinib dose
0 100 mg BID
-1 100 mg Daily
-2 Discontinue

 

Toxicity Toxicity Occurrence

Action

Grade ≥ 3 non-hematologic toxicities 

OR

Grade 3 thrombocytopenia with significant bleeding

OR

Grade 4 thrombocytopenia

OR

Grade 4 neutropenia lasting longer than 7 days

First and second

Hold until toxicity is Grade 1 or baseline.

Resume at same dose.

Third

Hold until toxicity is Grade 1 or baseline.

Resume at 1 dose level ↓.

Fourth Discontinue.

 



Dosage with Hepatic Impairment:

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.


Dosage with Renal Impairment:

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.



Dosage in the elderly:

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.

 



Children:

Safety and efficacy in children have not been established.



 
F - Administration Guidelines

  • Administer acalabrutinib with or without food. 
  • Capsules should be swallowed whole with a glass of water. Do not crush, dissolve or open capsules.
  • 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.
  • Store at room temperature, in original bottle, and away from children or pets.

 



 
G - Special Precautions
Contraindications:

  • Patients who are hypersensitive to acalabrutinib or to any ingredient in the formulation or component of the container. 

Other Warnings/Precautions:

  • 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.

Pregnancy and Lactation:
  • Fetotoxicity: 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: Unknown

    Breastfeeding is not recommended during treatment and for 2 weeks after receiving the last dose.

  • Fertility effects: Unlikely

    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.

 
H - Interactions

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.

AGENT EFFECT MECHANISM MANAGEMENT
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.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and at each visit

Renal and liver function tests

Baseline and at each visit

ECG

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



 
K - References

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.


April 2020 New drug monograph

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.