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Calquence

Generic Name: Acalabrutinib
Class: Antineoplastic Agents
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 on Oct 8, 2018

Antineoplastic agent; small-molecule inhibitor of Bruton's tyrosine kinase (BTK).1 2 4 5

Uses for Calquence

Mantle Cell Lymphoma

Treatment of mantle cell lymphoma in patients who have received at least one prior therapy;1 2 designated an orphan drug by FDA for this use.3

Current indication based on overall response rate; clinical benefit (e.g., increased survival) not established.1 2 Continued FDA approval for this indication may be contingent on verification and description of clinical benefit in additional trials.1

In the principal efficacy trial (ACE-LY-004 trial), the investigator-assessed overall response rate was 81%; 40% of patients achieved a complete response.1 2

Calquence Dosage and Administration

General

  • May increase the risk of infectious complications.1 In patients at increased risk for opportunistic infections, consider antimicrobial prophylaxis.1 9 (See Infectious Complications under Cautions.)

  • Acalabrutinib can potentially interact with drugs affecting gastric acidity, including antacids, histamine H2-receptor antagonists, and proton-pump inhibitors.1 See Interactions for further information and management recommendations (including timing of administration).

Restricted Distribution

  • Obtain acalabrutinib through specialty pharmacies and distributors.8 Consult AstraZeneca Access360 at 844-275-2360 or at [Web] for specific availability information.8

Administration

Oral Administration

Administer acalabrutinib capsules orally twice daily, approximately 12 hours apart, without regard to meals.1

Swallow capsules whole with water; do not open, break, or chew.1

If a dose is missed by >3 hours, skip that dose and take the next dose at the regularly scheduled time.1 Do not take extra capsules to make up for missed dose.1

Dosage

Adults

Mantle Cell Lymphoma
Oral

100 mg twice daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 2

Dosage Modification for Toxicity

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.1 Following recovery from toxicity (i.e., return to baseline or resolution to grade 1), resume (or discontinue) therapy as described in Table 1.1

Table 1: Recommended Dosage Modifications for Acalabrutinib Toxicity

Toxicity Occurrence

Dosage Modification 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

Avoid concomitant use with potent inhibitors of CYP3A; if short-term (i.e., ≤7 days) therapy is necessary, withhold acalabrutinib during such therapy.1 If used concomitantly with a moderate CYP3A inhibitor, reduce acalabrutinib dosage to 100 mg once daily.1 (See Interactions.)

Avoid concomitant use with potent inducers of CYP3A.1 If concomitant use cannot be avoided, increase acalabrutinib dosage to 200 mg twice daily.1 (See Interactions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No special dosage recommendations; most patients in pivotal efficacy study were geriatric.1 2 (See Geriatric Use under Cautions.)

Cautions for Calquence

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hemorrhage

Serious hemorrhagic events, including fatal cases, observed.1 2 Serious (grade 3 or higher) bleeding events, including GI bleeding, intracranial bleeding, and epistaxis, reported in 2% of patients treated with acalabrutinib monotherapy.1 2

Increased risk of hemorrhagic events with concomitant use of acalabrutinib and antiplatelet or anticoagulant therapies.1 Monitor patients for signs of bleeding during concurrent use.1

Consider potential benefits and risks of withholding acalabrutinib therapy for 3–7 days prior to and following surgery.1

Infectious Complications

Serious and sometimes fatal infections, including bacterial, fungal, viral, or other opportunistic infections, observed.1 2

Most commonly reported grade 3 or 4 infection was pneumonia.1 2 Infections caused by hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML) also observed.1

Consider antimicrobial prophylactic therapy in patients at increased risk for opportunistic infections.1 9

Monitor for signs and symptoms of infection during therapy and treat as medically appropriate.1

Myelosuppression

Cytopenias, including neutropenia, anemia, and thrombocytopenia, reported.1 Serious (grade 3 or 4) cytopenias observed.1

Monitor CBC counts monthly.1 If myelosuppression occurs, interrupt therapy and/or reduce dosage.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Development of Second Primary Malignancy

Second primary malignancies, including non-skin carcinomas, reported in 11% of acalabrutinib-treated patients.1 Skin cancer was the most frequently reported second primary malignancy, occurring in 7% of acalabrutinib-treated patients.1 (See Advice to Patients.)

Atrial Fibrillation and Flutter

Atrial fibrillation and atrial flutter observed.1

Monitor for development of atrial fibrillation and flutter and manage appropriately.1 (See Advice to Patients.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity (e.g., decreased fetal body weight, delayed skeletal ossification) observed in animals.1

If used during pregnancy, apprise of potential fetal hazard.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Acalabrutinib and its active metabolite (ACP-5862) distribute into milk in animals.1 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.1 Women should not breast-feed during therapy and for ≥2 weeks following drug discontinuance.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In clinical studies in patients with mantle cell lymphoma, approximately 65% of patients were ≥65 years of age and approximately 26% were ≥75 years of age.1 2 No clinically important differences in safety and efficacy compared with younger adults.1 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Mild or moderate hepatic impairment does not substantially alter pharmacokinetics.1 (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment.1

Renal Impairment

Mild to moderate renal impairment does not substantially alter pharmacokinetics of acalabrutinib; the drug is minimally excreted in urine.1

Not studied in patients with severe renal impairment or in patients with renal impairment undergoing dialysis.1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Previously treated mantle cell lymphoma: Anemia,1 2 thrombocytopenia,1 neutropenia,1 2 headache (often transient and usually occurring early during therapy),1 2 diarrhea,1 2 fatigue,1 2 myalgia,1 2 bruising.1

Interactions for Calquence

Principally metabolized by CYP3A and, to a minor extent, by glutathione conjugation and amide hydrolysis.1 Metabolism to the principal active metabolite (ACP-5862) mediated principally by CYP3A.1

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 2B6.1 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 CYP3A4.1

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 OATP1B3.1 Does not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3 at clinically relevant concentrations.1

CYP3A Inhibitors

Possible pharmacokinetic interaction (increased plasma acalabrutinib concentrations and risk of toxicity).1 Potent CYP3A inhibitors may substantially increase peak plasma concentrations and AUC of acalabrutinib.1 Moderate CYP3A inhibitors may increase peak plasma concentrations and AUC of acalabrutinib by twofold to almost threefold.1 (See Specific Drugs under Interactions.)

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.1 6 7

If used concomitantly with a moderate CYP3A inhibitor, reduce acalabrutinib dosage to 100 mg once daily.1 6

CYP3A Inducers

Possible pharmacokinetic interaction (decreased plasma acalabrutinib concentrations and reduced efficacy).1 (See Specific Drugs under Interactions.)

Avoid concomitant use with potent CYP3A inducers, if possible; if concomitant use cannot be avoided, increase acalabrutinib dosage to 200 mg twice daily.1 6 7

CYP Substrates

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely at clinically relevant concentrations.1

Substrates of BCRP

Possible pharmacokinetic interaction (increased exposure to BCRP substrates due to inhibition of intestinal BCRP).1 6 (See Specific Drugs under Interactions.)

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.1 6 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.1 6 (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Antacids

Possible decreased plasma concentrations and reduced efficacy of acalabrutinib1

Calcium carbonate: Decreased acalabrutinib AUC by 53%1

Antacids may be used as an alternative to proton-pump inhibitors; if concurrent use is necessary, separate antacid and acalabrutinib doses by ≥2 hours1

Anticoagulants

Increased risk of hemorrhagic events1

Monitor for signs of bleeding/hemorrhage1

Anticonvulsants (carbamazepine, phenytoin)

Possibly decreased plasma concentrations and reduced efficacy of acalabrutinib1 6 7

Avoid concomitant use; if concomitant use unavoidable, increase acalabrutinib dosage to 200 mg twice daily1

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

Possibly increased peak plasma concentrations and systemic exposure of acalabrutinib1

Itraconazole: Increased acalabrutinib peak plasma concentrations and AUC by 3.9- and 5.1-fold, respectively1

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 antifungal1 7

Moderate CYP3A inhibitors (e.g., fluconazole): Reduce acalabrutinib dosage to 100 mg once daily1 7

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased plasma concentrations and reduced efficacy of acalabrutinib1

Rifampin: Decreased acalabrutinib peak plasma concentration and AUC by 68 and 77%, respectively1

Avoid concomitant use; if concomitant use unavoidable, increase acalabrutinib dosage to 200 mg twice daily1

Antiplatelet agents

Increased risk of hemorrhagic events1

Monitor for signs of bleeding/hemorrhage1

Diltiazem

Possibly increased peak plasma concentrations and systemic exposure of acalabrutinib1

Reduce acalabrutinib dosage to 100 mg once daily1 6

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

Possible decreased plasma concentrations and reduced efficacy of acalabrutinib1

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 antagonist1

Macrolides (clarithromycin, erythromycin)

Possibly increased peak plasma concentrations and systemic exposure of acalabrutinib1

Erythromycin: Expected to increase peak plasma concentration and systemic exposure of acalabrutinib by twofold to almost threefold1

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 macrolide1 7

Moderate CYP3A inhibitors (e.g., erythromycin): Reduce acalabrutinib dosage to 100 mg once daily1 7

Methotrexate

Possible increased exposure to methotrexate (a BCRP substrate)1 6

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

Possible decreased plasma concentrations and efficacy of acalabrutinib1

Omeprazole: Decreased acalabrutinib AUC by 43%1

Avoid concomitant use1

Calquence Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration,1 4 with median time to peak plasma concentrations of 0.75 hours.1 Mean absolute bioavailability is 25%.1

Exhibits almost linear pharmacokinetics over a dosage range of 75–250 mg and dose proportionality.1 Accumulation does not appear to occur with repeated dosing.5

Duration

Median steady-state binding of acalabrutinib to BTK (BTK occupancy) of ≥95% is maintained over a 12-hour dosing interval.1 2

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.1

Special Populations

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: In a hepatic impairment study, exposure increased by less than twofold.1 Based on population pharmacokinetic analysis, pharmacokinetics of acalabrutinib did not differ in individuals with mild or moderate hepatic impairment (total bilirubin concentrations 1.5–3 times the ULN with any AST concentration) compared with individuals with normal hepatic function.1

Severe hepatic impairment (Child-Pugh class C or total bilirubin concentrations 3–10 times the ULN with any AST concentration): Not studied.1

Mild or moderate renal impairment (estimated GFR ≥30 mL/minute per 1.73 m2): Pharmacokinetics not substantially affected.1

Severe renal impairment (estimated GFR <29 mL/minute per 1.73 m2): Not studied.1

Age, body weight, gender, and race do not have clinically important effects on pharmacokinetics.1

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.1

Plasma Protein Binding

97.5%.1

Elimination

Metabolism

Metabolized principally by CYP3A and, to a minor extent, by glutathione conjugation and amide hydrolysis.1 Principal active metabolite is ACP-5862.1 Exposure to ACP-5682 is approximately two- to threefold higher than acalabrutinib exposure.1 ACP-5862 is approximately 50% less potent than acalabrutinib as a BTK inhibitor.1

Elimination Route

Eliminated in feces (84%) and urine (12%), mainly as metabolites; <1% excreted as unchanged drug.1

Half-life

Acalabrutinib: Median of 0.9 hours (range: 0.6–2.8 hours).1

ACP-5862 (active metabolite): 6.9 hours.1

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Selectively and irreversibly inhibits BTK, an essential signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.1

  • 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.1

  • Within B cells, BTK signaling results in activation of pathways involved in cell proliferation, trafficking, chemotaxis, and adhesion.1 In nonclinical studies, acalabrutinib inhibited the BTK-mediated activation of downstream signaling proteins CD86 and CD69 resulting in decreased malignant B-cell proliferation and survival.1 4 5

  • Inhibition of BTK also reduces plasma concentrations of cytokines and chemokines, which may lead to decreased cell adhesion and mobilization of cells from tissues.2 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).2 6

  • 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).2 4 5 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.2 4 5

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information.1

  • Importance of advising patients to take acalabrutinib as directed by their clinician.1 If a dose is missed, importance of administering the next dose as soon as it is remembered.1 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.1 An extra dose should not be taken to make up for a missed dose.1

  • Importance of advising patients to swallow acalabrutinib capsules whole with a glass of water and not to open, break, or chew the capsules.1

  • Risk of bleeding/hemorrhage.1 Importance of informing clinician if signs or symptoms of severe bleeding occur (e.g., blood in stool or urine; unexpected, prolonged, or uncontrolled bleeding).1 Importance of informing patients that acalabrutinib therapy may need to be interrupted for major surgeries.1

  • Risk of serious infection.1 Importance of promptly reporting signs or symptoms of possible infection (e.g., fever, chills, flu-like symptoms).1

  • Risk of myelosuppression.1 Importance of informing patients that periodic CBC counts are necessary during acalabrutinib therapy.1

  • Possible risk of developing a second primary malignancy (e.g., skin cancer).1 Importance of advising patients to protect skin from the sun.1

  • Risk of atrial fibrillation and flutter.1 Importance of informing clinician if palpitations, lightheadedness, dizziness, fainting, shortness of breath, or chest discomfort occurs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Apprise patient of potential hazard to the fetus if used during pregnancy.1

  • Importance of advising women to avoid breast-feeding while receiving acalabrutinib and for ≥2 weeks after discontinuance of therapy.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (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.8 (See Restricted Distribution under Dosage and Administration.)

Acalabrutinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg

Calquence

AstraZeneca

AHFS DI Essentials™. © Copyright 2018, Selected Revisions October 8, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals LP. Calquence (acalabrutinib) gelatin-coated capsules prescribing information. Wilmington, DE; 2017 Nov.

2. Wang M, Rule S, Zinzani PL et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018; 391:659-67. http://www.ncbi.nlm.nih.gov/pubmed/29241979?dopt=AbstractPlus

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2017 Dec 27. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

4. Barf T, Covey T, Izumi R et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017; 363:240-52.

5. Byrd JC, Harrington B, O'Brien S et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016; 374:323-32.

6. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210259Orig1s000: Multi-discipline review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf

7. US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. From FDA website. Accessed 2018 Jul 9. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm

8. AstraZeneca Pharmaceuticals LP. Calquence (acalabrutinib) distribution card. 2018. From the AstraZeneca Access 360 website. Accessed 2018 Jul 5. https://www.calquence.com/content/dam/physician-services/us/484-hcp-acalabranded/pdf/hcp/how_to_order_calquence.pdf

9. Awan FT, Jurczak W. Use of acalabrutinib in patients with mantle cell lymphoma. Expert Rev Hematol. 2018; 11:495-502. http://www.ncbi.nlm.nih.gov/pubmed/29737219?dopt=AbstractPlus

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