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Acalabrutinib

Brand name: Calquence
Drug class: Antineoplastic Agents
- Bruton's Tyrosine Kinase Inhibitors
- Bruton Tyrosine Kinase Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: 4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]-pyrazin-1-yl]-N-2-pyridinyl-benzamide
Molecular formula: C26H23N7O2
CAS number: 1420477-60-6

Medically reviewed by Drugs.com on Mar 30, 2022. Written by ASHP.

Introduction

Antineoplastic agent; small-molecule inhibitor of Bruton's tyrosine kinase (BTK).

Uses for Acalabrutinib

Mantle Cell Lymphoma

Treatment of mantle cell lymphoma in patients who have received at least one prior therapy; designated an orphan drug by FDA for this use.

Current indication based on overall response rate; clinical benefit (e.g., increased survival) not established. Continued FDA approval for this indication may be contingent on verification and description of clinical benefit in additional trials.

In the principal efficacy trial (ACE-LY-004 trial), the investigator-assessed overall response rate was 81%; 40% of patients achieved a complete response.

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Treatment of CLL or SLL; designated an orphan drug by FDA for treatment of CLL.

Acalabrutinib Dosage and Administration

General

Pretreatment Screening

  • Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Patient Monitoring

  • Monitor for signs and symptoms of infection during therapy and treat promptly if infection occurs.

  • Monitor patients for signs of bleeding and manage appropriately.

  • Monitor CBC counts during therapy.

  • Monitor for development of skin cancers.

  • Monitor for symptoms of arrhythmias and manage appropriately.

Premedication and Prophylaxis

  • In patients at increased risk for opportunistic infections, consider antimicrobial prophylaxis.

Other General Considerations

  • Consider potential benefits and risks of withholding acalabrutinib therapy for 3–7 days prior to and following surgery (based on the type of surgery and bleeding risk).

  • Use sun protection.

Administration

Oral Administration

Administer acalabrutinib capsules orally twice daily, approximately 12 hours apart, without regard to meals.

Swallow capsules whole with water; do not open, break, or chew.

If a dose is missed by >3 hours, skip that dose and take the next dose at the regularly scheduled time. Do not take extra capsules to make up for missed dose.

Dosage

Adults

Mantle Cell Lymphoma
Oral

100 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

CLL/SLL
Monotherapy
Oral

100 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Combination Therapy with Obinutuzumab
Oral

Previously untreated CLL or SLL: 100 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Initiate acalabrutinib at cycle 1; initiate obinutuzumab at cycle 2, for a total of six 28-day cycles.

Consult obinutuzumab prescribing information for recommended dosage.

When given on the same day, administer acalabrutinib prior to obinutuzumab.

Dosage Modification for Toxicity
Oral

If grade 3 or greater nonhematologic toxicity, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia lasting >7 days occurs, interrupt therapy. Following recovery from toxicity (i.e., return to baseline or resolution to grade 1), resume (or discontinue) therapy as described in Table 1.

Table 1: Recommended Dosage Modifications for Acalabrutinib Toxicity

Toxicity Occurrence

Recommended Dosage after Recovery from Toxicity – (Starting Dosage = 100 mg twice daily)

First

Restart at 100 mg twice daily

Second

Restart at 100 mg twice daily

Third

Restart at 100 mg once daily

Fourth

Discontinue acalabrutinib

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Oral

Avoid concomitant use with potent inhibitors of CYP3A; if short-term (i.e., ≤7 days) therapy is necessary, withhold acalabrutinib during such therapy. If used concomitantly with a moderate CYP3A inhibitor, reduce acalabrutinib dosage to 100 mg once daily.

Avoid concomitant use with potent inducers of CYP3A. If concomitant use cannot be avoided, increase acalabrutinib dosage to 200 mg twice daily.

Concomitant Use with Gastric Acidity
Oral

Take acalabrutinib 2 hours before taking a histamine H2-receptor antagonist.

Separate administration of antacid and acalabrutinib by ≥2 hours.

Avoid concomitant use of acalabrutinib with proton-pump inhibitors.

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild or moderate hepatic impairment.

Avoid use in patients with severe hepatic impairment.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No special dosage recommendations.

Cautions for Acalabrutinib

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Infectious Complications

Serious and sometimes fatal infections, including bacterial, fungal, viral, or other opportunistic infections, observed.

Most commonly reported grade 3 or 4 infections were respiratory tract infections including pneumonia. Infections caused by hepatitis B reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML) also observed.

Consider anti-infective prophylactic therapy in patients at increased risk for opportunistic infections.

Monitor for signs and symptoms of infection during therapy and treat promptly if infection occurs.

Hemorrhage

Serious hemorrhagic events, including fatal cases, observed. Major hemorrhage (serious or grade 3 or higher bleeding or any CNS system bleeding) reported in 3% of patients treated with acalabrutinib in clinical trials.

Increased risk of hemorrhagic events with concomitant use of acalabrutinib and antithrombotic agents. Consider risks and benefits and monitor patients for signs of bleeding during concurrent use.

Consider potential benefits and risks of withholding acalabrutinib therapy for 3–7 days prior to and following surgery.

Myelosuppression

Cytopenias, including neutropenia, anemia, thrombocytopenia, and lymphopenia, reported. Serious (grade 3 or 4) cytopenias observed.

Monitor CBC counts regularly. If myelosuppression occurs, interrupt therapy, reduce dosage, or discontinue therapy as appropriate.

Development of Second Primary Malignancy

Second primary malignancies, including skin cancers and other solid tumors, reported in 12% of acalabrutinib-treated patients. Skin cancer was the most frequently reported second primary malignancy, occurring in 6% of acalabrutinib-treated patients.

Monitor patients for skin cancers and advise patients to avoid sun exposure.

Atrial Fibrillation and Flutter

Atrial fibrillation and atrial flutter observed.

Risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, or acute infection.

Monitor for symptoms of arrhythmias and manage appropriately.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm and dystocia. Embryofetal toxicity (e.g., decreased fetal body weight, delayed skeletal ossification) observed in animals.

If used during pregnancy, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm and dystocia.

Lactation

Acalabrutinib and its active metabolite (ACP-5862) distribute into milk in animals. Not known whether the drug or its active metabolite distributes into human milk or if drug has any effect on milk production or the nursing infant. Women should not breast-feed during therapy and for ≥2 weeks following drug discontinuance.

Females and Males of Reproductive Potential

Pregnancy testing recommended for females of reproductive potential prior to initiating acalabrutinib therapy.

Advise female patients of reproductive potential to use effective contraception during treatment with acalabrutinib and for ≥1 week following the last dose of the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In clinical studies in patients with mantle cell lymphoma or CLL, approximately 68% of patients were ≥65 years of age and approximately 24% were ≥75 years of age. No clinically important differences in efficacy compared with younger adults.

Among patients ≥65 years of age, 59% had grade 3 or higher adverse reactions and 39% had serious adverse reactions. Among patients <65 years of age, 45% had grade 3 or higher adverse reactions and 25% had serious adverse reactions.

Hepatic Impairment

Mild or moderate hepatic impairment does not substantially alter pharmacokinetics.

Safety not evaluated in patients with moderate or severe hepatic impairment. Avoid use in patients with severe hepatic impairment.

Renal Impairment

Mild to moderate renal impairment does not substantially alter pharmacokinetics of acalabrutinib.

Not studied in patients with severe renal impairment or in patients with renal impairment undergoing dialysis.

Common Adverse Effects

Adverse effects (reported in ≥30% of patients): Anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, musculoskeletal pain.

Interactions for Acalabrutinib

Principally metabolized by CYP3A and, to a minor extent, by glutathione conjugation and amide hydrolysis. Metabolism to the principal active metabolite (ACP-5862) mediated principally by CYP3A.

Acalabrutinib is a weak inhibitor of CYP3A4/5, 2C8, and 2C9; does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, and 2D6; and is a weak inducer of CYP isoenzymes 3A4, 1A2, and 2B6. ACP-5862 is a weak inhibitor of CYP isoenzymes 2C8, 2C9, and 2C19; does not inhibit CYP isoenzymes 3A4/5, 1A2, 2B6, and 2D6; and is a weak inducer of CYP3A4.

Acalabrutinib and ACP-5862 do not inhibit uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1 or UGT2B7.

Acalabrutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, and organic anion transport proteins (OATP) 1B1 and OATP1B3. May inhibit intestinal BCRP. Does not inhibit P-gp, multidrug and toxin extrusion transporter (MATE) 1, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3 at clinically relevant concentrations.

ACP-5862 is a substrate of P-gp and BCRP but is not a substrate of OATP1B1 or OATP1B3. May inhibit MATE1. Does not inhibit BCRP, P-gp, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3 at clinically relevant concentrations.

CYP3A Inhibitors

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma acalabrutinib concentrations and risk of toxicity). Avoid concomitant use with potent CYP3A inhibitors, if possible; if short-term (≤7 days) administration of a potent CYP3A inhibitor is required, withhold acalabrutinib during such administration.

Moderate CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma acalabrutinib concentrations and risk of toxicity). If used concomitantly with a moderate CYP3A inhibitor, reduce acalabrutinib dosage to 100 mg once daily.

CYP3A Inducers

Possible pharmacokinetic interaction (decreased plasma acalabrutinib concentrations and reduced efficacy).

Avoid concomitant use with potent CYP3A inducers, if possible; if concomitant use cannot be avoided, increase acalabrutinib dosage to 200 mg twice daily.

CYP Substrates

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely at clinically relevant concentrations.

Substrates of BCRP

Possible pharmacokinetic interaction (increased exposure to BCRP substrates due to inhibition of intestinal BCRP).

Substrates of MATE1

Possible pharmacokinetic interaction (increased exposure to MATE1 substrates due to inhibition of MATE1 by ACP-5862).

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased solubility of acalabrutinib may result in decreased plasma concentrations and reduced efficacy) with drugs that increase gastric pH. If therapy with an acid suppressive agent is necessary in a patient receiving acalabrutinib, consider use of a histamine H2-receptor antagonist (e.g., famotidine, ranitidine) or an antacid (e.g., calcium carbonate) instead of a proton-pump inhibitor.

Specific Drugs

Drug

Interaction

Comments

Antacids

Possible decreased plasma concentrations and reduced efficacy of acalabrutinib

Calcium carbonate: Decreased acalabrutinib AUC by 53%

Antacids may be used as an alternative to proton-pump inhibitors; if concurrent use is necessary, separate antacid and acalabrutinib doses by ≥2 hours

Anticoagulants

Increased risk of hemorrhagic events

Monitor for signs of bleeding/hemorrhage

Anticonvulsants (carbamazepine, phenytoin)

Possible decreased plasma concentrations and reduced efficacy of acalabrutinib

Avoid concomitant use; if concomitant use unavoidable, increase acalabrutinib dosage to 200 mg twice daily

Antifungals, azole (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased peak plasma concentrations and systemic exposure of acalabrutinib

Itraconazole: Increased acalabrutinib peak plasma concentrations and AUC by 3.9- and 5.1-fold, respectively

Potent CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole): Avoid concomitant use; if concomitant use of the antifungal is short term (≤7 days), withhold acalabrutinib therapy during administration of the antifungal

Moderate CYP3A inhibitors (e.g., fluconazole): Reduce acalabrutinib dosage to 100 mg once daily

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased plasma concentrations and reduced efficacy of acalabrutinib

Rifampin: Decreased acalabrutinib peak plasma concentration and AUC by 68 and 77%, respectively

Avoid concomitant use; if concomitant use unavoidable, increase acalabrutinib dosage to 200 mg twice daily

Antiplatelet agents

Increased risk of hemorrhagic events

Monitor for signs of bleeding/hemorrhage

Diltiazem

Possible increased peak plasma concentrations and systemic exposure of acalabrutinib

Reduce acalabrutinib dosage to 100 mg once daily

Histamine H2-receptor antagonists (e.g., cimetidine, famotidine, ranitidine)

Possible decreased plasma concentrations and reduced efficacy of acalabrutinib

H2-receptor antagonists may be used as an alternative to proton-pump inhibitors; if concurrent use is necessary, administer acalabrutinib 2 hours before the H2-receptor antagonist

Macrolides (clarithromycin, erythromycin)

Possible increased peak plasma concentrations and systemic exposure of acalabrutinib

Erythromycin: Expected to increase peak plasma concentration and systemic exposure of acalabrutinib by twofold to almost threefold

Potent CYP3A inhibitors (e.g., clarithromycin): Avoid concomitant use; if concomitant use of the macrolide is short term (≤7 days), withhold acalabrutinib therapy during administration of the macrolide

Moderate CYP3A inhibitors (e.g., erythromycin): Reduce acalabrutinib dosage to 100 mg once daily

Metformin

Possible increased exposure to metformin (MATE1 substrate)

Methotrexate

Possible increased exposure to methotrexate (a BCRP substrate)

Proton-pump inhibitors (e.g., omeprazole)

Possible decreased plasma concentrations and efficacy of acalabrutinib

Omeprazole: Decreased acalabrutinib AUC by 43%

Avoid concomitant use

Acalabrutinib Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with median time to peak plasma concentrations of 0.9 hours for acalabrutinib and 1.6 hours for ACP-5862, the active metabolite. Mean absolute bioavailability is 25%.

Exhibits dose-proportionality; exposures of both acalabrutinib and ACP-5862 increase with dose over a dosage range of 75–250 mg. Accumulation does not appear to occur with repeated dosing.

Duration

Median steady-state binding of acalabrutinib to BTK (BTK occupancy) of ≥95% is maintained over a 12-hour dosing interval.

Food

High-fat, high-calorie meal did not substantially alter AUC; peak plasma concentrations decreased by 73% and time to achieve peak concentrations delayed by 1–2 hours compared with administration under fasting conditions.

Special Populations

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Systemic exposure increased by 1.9-fold or 1.5-fold in individuals with mild or moderate hepatic impairment, respectively. Pharmacokinetics of acalabrutinib or ACP-5862 (active metabolite) did not differ in individuals with mild or moderate hepatic impairment (total bilirubin concentrations ≤ULN with AST concentration >ULN or total bilirubin concentrations >ULN with any AST concentration) compared with individuals with normal hepatic function.

Severe hepatic impairment (Child-Pugh class C): Systemic exposure increased by 5.3-fold. No clinically important differences in pharmacokinetics of ACP-5862 (active metabolite) observed.

Mild or moderate renal impairment (estimated GFR ≥30 mL/minute per 1.73 m2): Pharmacokinetics not substantially affected.

Severe renal impairment (estimated GFR <29 mL/minute per 1.73 m2): Not studied.

Age, body weight, sex, and race do not have clinically important effects on pharmacokinetics.

Distribution

Extent

Acalabrutinib and its active metabolite ACP-5862 distribute into milk in animals; not known whether the drug and/or its active metabolite distributes into human milk.

Plasma Protein Binding

Acalabrutinib: 97.5%.

ACP-5862 (active metabolite): 98.6%.

Elimination

Metabolism

Metabolized principally by CYP3A and, to a minor extent, by glutathione conjugation and amide hydrolysis. Principal active metabolite is ACP-5862. Exposure to ACP-5682 is approximately two- to threefold higher than acalabrutinib exposure. ACP-5862 is approximately 50% less potent than acalabrutinib as a BTK inhibitor.

Elimination Route

Eliminated in feces (84%) and urine (12%), mainly as metabolites; <2% excreted in urine and feces as unchanged drug.

Half-life

Acalabrutinib: Mean of 1 hour.

ACP-5862 (active metabolite): Mean of 3.5 hours.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Actions

  • Selectively and irreversibly inhibits BTK, an essential signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.

  • Acalabrutinib and its active metabolite (ACP-5862) bind covalently with a cysteine residue in the BTK active site resulting in inhibition of BTK enzymatic activity.

  • Within B cells, BTK signaling results in activation of pathways involved in cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited the BTK-mediated activation of downstream signaling proteins CD86 and CD69 resulting in decreased malignant B-cell proliferation and tumor growth in mouse xenograft models.

  • Inhibition of BTK also reduces plasma concentrations of cytokines and chemokines, which may lead to decreased cell adhesion and mobilization of cells from tissues. This redistribution of cells from tissues to peripheral blood may contribute to the transient increase in absolute lymphocyte count (lymphocytosis) observed in patients receiving BTK inhibitors (e.g., acalabrutinib, ibrutinib).

  • Unlike ibrutinib (another BTK inhibitor used to treat mantle cell lymphoma), acalabrutinib does not appear to irreversibly target kinases other than BTK, including epidermal growth factor receptor (EGFR), tyrosine kinase expressed in hepatocellular carcinoma (TEC), and interleukin 2-inducible T-cell kinase (ITK). The selective targeting of BTK by acalabrutinib may help explain, at least in part, certain tolerability differences observed between acalabrutinib and ibrutinib in clinical studies to date.

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information.

  • Importance of advising patients to take acalabrutinib as directed by their clinician. If a dose is missed, importance of administering the next dose as soon as it is remembered. However, if it has been more than 3 hours, importance of skipping the missed dose and taking the next dose at the regularly scheduled time. An extra dose should not be taken to make up for a missed dose.

  • Importance of advising patients to swallow acalabrutinib capsules whole with a glass of water and not to open, break, or chew the capsules.

  • Risk of bleeding/hemorrhage. Importance of informing clinician if signs or symptoms of bleeding occur. Importance of informing patients that acalabrutinib therapy may need to be interrupted for major surgeries.

  • Risk of serious infection. Importance of promptly reporting signs or symptoms of possible infection (e.g., fever, chills, flu-like symptoms).

  • Risk of myelosuppression. Importance of informing patients that periodic CBC counts are necessary during acalabrutinib therapy.

  • Possible risk of developing a second primary malignancy (e.g., skin cancer, other solid tumors). Importance of advising patients to protect skin from the sun.

  • Risk of atrial fibrillation and flutter. Importance of informing clinician if palpitations, dizziness, fainting, shortness of breath, or chest discomfort occurs.

  • Importance of females informing clinicians if they are or plan to become pregnant or plan to breast-feed. Apprise patient of potential hazard to the fetus and risk of dystocia if used during pregnancy. Advise females to avoid becoming pregnant while receiving acalabrutinib and for ≥1 week after discontinuance of therapy.

  • Importance of advising females to avoid breast-feeding while receiving acalabrutinib and for ≥2 weeks after discontinuance of therapy.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., anticoagulant or antiplatelet drugs, antacids, histamine H2-receptor antagonists, proton-pump inhibitors) and dietary or herbal supplements, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Distribution of acalabrutinib is restricted. Consult manufacturer's website for specific availability information.

Acalabrutinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg

Calquence

AstraZeneca

AHFS DI Essentials™. © Copyright 2022, Selected Revisions March 30, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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