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Calquence

Generic Name: Acalabrutinib
Class: Antineoplastic Agents
Chemical Name: 4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide
Molecular Formula: C26H23N7O2
CAS Number: 1420477-60-6

Medically reviewed on November 6, 2017

Introduction

Acalabrutinib is an antineoplastic agent.

Uses for Calquence

Acalabrutinib has the following uses:

Acalabrutinib is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. 1

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1

Calquence Dosage and Administration

General

Acalabrutinib is available in the following dosage form(s) and strength(s):

Capsules: 100 mg. 1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Recommended dose is 100 mg orally approximately every twelve hours; swallow whole with water and with or without food. 1

  • Advise patients not to break, open, or chew capsules. 1

  • Consult manufacturer's labeling for information on management of toxicities using treatment interruption, dose reduction, or discontinuation. 1

Cautions for Calquence

Contraindications

None. 1

Warnings/Precautions

Hemorrhage

Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with acalabrutinib monotherapy. Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis have been reported in 2% of patients. Overall, bleeding events including bruising and petechiae of any grade occurred in approximately 50% of patients with hematological malignancies.1

The mechanism for the bleeding events is not well understood. Acalabrutinib may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding acalabrutinib for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.1

Infection

Serious infections (bacterial, viral, or fungal), including fatal events and opportunistic infections have occurred in the combined safety database of 612 patients with hematologic malignancies treated with acalabrutinib monotherapy. Consider prophylaxis in patients who are at increased risk for opportunistic infections.1

Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or 4 infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred. Monitor patients for signs and symptoms of infection and treat as medically appropriate.1

Cytopenias

In the combined safety database of 612 patients with hematologic malignancies, patients treated with acalabrutinib monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%) and thrombocytopenia (8%) based on laboratory measurements. In the acalabrutinib clinical Trial LY-004, patients’ complete blood counts were assessed monthly during treatment.1

Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies treated with acalabrutinib monotherapy in the combined safety database of 612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise protection from sun exposure.1

Atrial Fibrillation and Flutter

In the combined safety database of 612 patients with hematologic malignancies treated with acalabrutinib monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.1

Specific Populations

Pregnancy

Based on findings in animals, acalabrutinib may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of acalabrutinib to pregnant rabbits during organogenesis resulted in reduced fetal growth at maternal exposures (AUC) approximately 4 times exposures in patients at the recommended dose of 100 mg twice daily). Advise pregnant women of the potential risk to a fetus.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 16-times the AUC in patients at the recommended dose of 100 mg twice daily. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma. In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses ≥ 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification. The AUC at 100 mg/kg/day in pregnant rabbits was approximately 4-times the AUC in patients at 100 mg twice daily.1

Lactation

No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. Due to the potential for adverse reactions in a breastfed child from acalabrutinib, advise lactating women not to breastfeed while taking acalabrutinib and for at least 2 weeks after the final dose.1

Pediatric Use

The safety and efficacy of acalabrutinib in pediatric patients have not been established.1

Geriatric Use

Eighty (64.5%) of the 124 mantle cell lymphoma (MCL) patients in clinical trials of acalabrutinib were 65 years of age or older, and 32 patients (25.8%) were 75 years of age or older. No clinically relevant differences in safety or efficacy were observed between patients ≥ 65 years and younger.1

Common Adverse Effects

Most common adverse reactions (reported in ≥ 20% of patients) were: anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. 1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A Inhibitors: Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended.1

  • CYP3A Inducers: Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended.1

  • Gastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists and antacids.1

Actions

Mechanism of Action

Acalabrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Inform patients to report signs or symptoms of severe bleeding. Inform patients that acalabrutinib may need to be interrupted for major surgeries.1

Inform patients to report signs or symptoms suggestive of infection.1

Inform patients that they will need periodic blood tests to check blood counts during treatment with acalabrutinib.1

Inform patients that other malignancies have been reported in patients who have been treated with acalabrutinib, including skin cancer. Advise patients to use sun protection.1

Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort.1

Instruct patients to take acalabrutinib orally twice daily, about 12 hours apart. Acalabrutinib may be taken with or without food. Advise patients that acalabrutinib capsules should be swallowed whole with a glass of water, without being opened, broken, or chewed.1

Advise patients that if they miss a dose of acalabrutinib, they may still take it up to 3 hours after the time they would normally take it. If more than 3 hours have elapsed, they should be instructed to skip that dose and take their next dose of acalabrutinib at the usual time. Warn patients they should not take extra capsules to make up for the dose that they missed.1

Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products.1

Advise women not to breastfeed during treatment with acalabrutinib and for at least 2 weeks after the final dose.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Acalabrutinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsule, Gelatin Coated

100 mg

Calquence

AstraZeneca Pharmaceuticals LP

AHFS Drug Information. © Copyright 2018, Selected Revisions November 6, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals LP. CALQUENCE (acalabrutinib) ORAL prescribing information. 2017 Oct. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dd4835ef-e1bc-4997-a399-1ffa2556fbfe

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