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Zanubrutinib

Class: Antineoplastic Agents
- Bruton's Tyrosine Kinase Inhibitors
- Bruton Tyrosine Kinase Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical Name: (7S)-2-(4-Phenoxyphenyl)-7-[1-(prop-2-enoyl)piperidin-4-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamid
Molecular Formula: C27H29N5O3
CAS Number: 1691249-45-2
Brands: Brukinsa

Medically reviewed by Drugs.com. Last updated on Sep 28, 2020.

Introduction

Antineoplastic agent; inhibitor of Bruton's tyrosine kinase (BTK).1 2 3 4 8 9

Uses for Zanubrutinib

Mantle Cell Lymphoma

Treatment of mantle cell lymphoma in patients who have received at least one prior therapy;1 2 3 designated an orphan drug by FDA for this cancer.5

Current indication based on overall response rate; improvement in overall survival not established.1 2 3 Continued FDA approval for this indication may be contingent on verification and description of clinical benefit in additional trials.1

Zanubrutinib Dosage and Administration

General

  • In patients at increased risk for infections, consider prophylaxis for herpes simplex virus (HSV) infection, Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP), and other infections according to current standards of care.1 (See Infectious Complications under Cautions.)

  • Monitor CBCs during therapy.1

Restricted Distribution

  • Obtain zanubrutinib through specialty pharmacies and distributors.6 Contact manufacturer for additional information.

Administration

Oral Administration

Administer once daily or in divided doses twice daily, without regard to meals.1

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

If a dose of zanubrutinib is missed, take the missed dose as soon as it is remembered on the same day.1 Take the next dose at the regularly scheduled time the following day.1

Dosage

Adults

Mantle Cell Lymphoma
Oral

320 mg daily (administered once daily or in divided doses twice daily).1 Continue therapy until disease progression or unacceptable toxicity occurs.1

If concomitant use with a potent or moderate CYP3A inhibitor is necessary, reduce zanubrutinib dosage.1 (See Interactions.)

Dosage Modification for Toxicity
Oral

If grade 3 or higher nonhematologic toxicity, grade 3 febrile neutropenia, grade 3 thrombocytopenia with significant bleeding, or prolonged (i.e., lasting >10 days) grade 4 thrombocytopenia or neutropenia occurs, temporarily interrupt therapy.1 Dosage modification may be necessary following recovery from toxicity (i.e., return to baseline or resolution to grade 1).1 (See Table 1.)

No dosage adjustment necessary in patients with asymptomatic lymphocytosis.1 (See Actions.)

Table 1: Recommended Dosage Modifications for Zanubrutinib Toxicity1

Dosage Modification after Recovery from Toxicity

Dosage Modification after Recovery from Toxicity

Toxicity Occurrence

Initial Dosage = 160 mg twice daily

Initial Dosage = 320 mg once daily

First

Resume at same dosage

Resume at same dosage

Second

Resume at 80 mg twice daily

Resume at 160 mg once daily

Third

Resume at 80 mg once daily

Resume at 80 mg once daily

Fourth

Discontinue zanubrutinib

Discontinue zanubrutinib

Prescribing Limits

Adults

Mantle Cell Lymphoma
Oral

Dosage <80 mg once daily not recommended.1

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Reduce dosage to 80 mg twice daily.1 Monitor for signs of toxicity.1 (See Hepatic Impairment under Cautions.)

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.1 Monitor for signs of toxicity.1

Renal Impairment

Severe renal impairment (Clcr <30 mL/minute) or patients receiving dialysis: No specific dosage recommendations at this time.1 Monitor for signs of toxicity.1 (See Renal Impairment under Cautions.)

Mild to moderate renal impairment (Clcr ≥30 mL/minute): No dosage adjustment required.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Zanubrutinib

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hemorrhage

Serious hemorrhagic events (i.e., intracranial or GI hemorrhage, hematuria, hemothorax), sometimes fatal, reported in zanubrutinib-treated patients with hematologic malignancies.1 Hemorrhagic events of any grade, including purpura and petechiae, reported in 50% of patients receiving zanubrutinib.1

Hemorrhagic events reported regardless of concomitant antiplatelet or anticoagulant therapy, but concomitant use may increase risk of hemorrhage.1

Consider potential benefits and risks of withholding zanubrutinib therapy for 3–7 days prior to and following surgery (based on the type of surgery and bleeding risk).1

Monitor for signs and symptoms of bleeding.1 If intracranial hemorrhage occurs, discontinue zanubrutinib.1

Infectious Complications

Serious and sometimes fatal infections, including bacterial, fungal, viral, or other opportunistic infections, reported in zanubrutinib-treated patients with hematologic malignancies.1 Most common grade 3 or higher infection is pneumonia.1 Infections caused by hepatitis B virus (HBV) reactivation also reported.1

Consider prophylaxis for HSV, PCP, and other infections in patients who are at increased risk for infections.1

Monitor for signs and symptoms of infection and initiate anti-infective treatment as clinically indicated.1

Hematologic Effects

Cytopenias, including neutropenia, thrombocytopenia, and anemia, reported.1

Monitor CBCs during therapy.1 If hematologic toxicity occurs, interruption of therapy followed by dosage reduction may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.) Initiate appropriate therapeutic measures (e.g., hematopoietic growth factor or transfusion) as necessary.1

Development of Second Primary Malignancy

Second primary malignancies, including non-skin carcinomas, reported in patients with hematologic malignancies receiving single-agent zanubrutinib.1 Skin cancer (basal cell carcinoma and squamous cell carcinoma) most frequently reported second primary malignancy.1 (See Advice to Patients.)

Atrial Fibrillation and Flutter

Atrial fibrillation and flutter reported.1 Increased risk in those with cardiac risk factors, hypertension, or acute infection.1

Monitor for manifestations of atrial fibrillation and flutter and institute appropriate management as necessary.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity (e.g., postimplantation loss) and teratogenicity (e.g., cardiac malformations) observed in animals.1

Avoid pregnancy during therapy.1 Women of reproductive potential should use effective contraceptive methods during therapy and for ≥1 week after the last dose.1 Men should avoid fathering a child during and for ≥1 week after the last dose.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

Not known whether zanubrutinib or its metabolites are distributed into human milk or if drug has any effect on milk production or nursing infant.1

Discontinue nursing during therapy and for ≥2 weeks after the last dose.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No clinically important differences in safety and efficacy compared with younger adults.1

Hepatic Impairment

Increased systemic exposure in patients with hepatic impairment.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Dosage adjustment required in patients with severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Monitor for toxicity in patients with mild or moderate hepatic impairment.1

Renal Impairment

Mild or moderate renal impairment (Clcr ≥30 mL/minute) does not substantially alter pharmacokinetics of zanubrutinib.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Limited data in patients with severe renal impairment (Clcr <30 mL/minute) and in those undergoing dialysis; monitor for toxicity.1

Common Adverse Effects

Decreased neutrophil count,1 decreased platelet count,1 upper respiratory tract infection,1 decreased WBC count,1 decreased hemoglobin concentration,1 rash,1 bruising,1 diarrhea,1 cough.1

Interactions for Zanubrutinib

Metabolized principally by CYP3A.1

In vitro, zanubrutinib induces CYP2B6.1 Weak inducer of CYP3A4 and 2C19 in vivo.7

Substrate and inhibitor of P-glycoprotein (P-gp); not a substrate or inhibitor of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, organic anion transport proteins (OATP) 1B1, or OATP1B3.1 7

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, zanubrutinib.1 If concomitant use is necessary, reduce once- or twice-daily zanubrutinib dosage to 80 mg once daily; monitor for signs of zanubrutinib toxicity and interrupt and reduce dosage accordingly (see Dosage Modification for Toxicity under Dosage and Administration).1 When concomitant use of the potent CYP3A inhibitor is discontinued, return zanubrutinib dosage to dosage used prior to initiation of the potent CYP3A inhibitor.1

Moderate inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, zanubrutinib.1 If concomitant use is necessary, reduce once- or twice-daily zanubrutinib dosage to 80 mg twice daily; monitor for signs of zanubrutinib toxicity and interrupt and reduce dosage accordingly (see Dosage Modification for Toxicity under Dosage and Administration).1 When concomitant use of the moderate CYP3A inhibitor is discontinued, return zanubrutinib dosage to dosage used prior to initiation of the moderate CYP3A inhibitor.1

Potent or moderate inducers of CYP3A: Possible decreased systemic exposure to, and decreased therapeutic efficacy of, zanubrutinib.1 Avoid concomitant use.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A or 2C19: Possible decreased systemic exposure of the substrate drug.1 7

Substrates of CYP2C9 or CYP2C8: No clinically meaningful effect on pharmacokinetics of the substrate drug.1

Substrates of Efflux Transport Systems

Substrates of P-gp: Possible increased systemic exposure of the substrate drug.1

Substrates of BCRP, OATP1B1, and OATP1B3: No clinically meaningful effect on pharmacokinetics of the substrate drug.1 7

Drugs Affecting Gastric Acidity

No clinically meaningful effect on pharmacokinetics of zanubrutinib.1

Specific Drugs

Drug

Interaction

Comments

Anticoagulants

Possible increased risk of hemorrhagic events (see Hemorrhage under Cautions)1

No clinically important effect on pharmacokinetics of warfarin1

Antifungals, azole (e.g., fluconazole, itraconazole)

Possible increased peak plasma concentration and systemic exposure of zanubrutinib1

Itraconazole: Increased zanubrutinib peak plasma concentration and AUC by 157 and 278%, respectively1 7

Fluconazole: Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 179–270 and 177–284%, respectively1 7

Potent CYP3A inhibitors (e.g., itraconazole): Reduce zanubrutinib once- or twice-daily dosage to 80 mg once daily1 7

Moderate CYP3A inhibitors (e.g., fluconazole): Reduce zanubrutinib once- or twice-daily dosage to 80 mg twice daily1 7

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased peak plasma concentration and AUC of zanubrutinib1

Rifampin decreased zanubrutinib peak plasma concentration and AUC by 92 and 93%, respectively1

Avoid concomitant use1

Antiplatelet agents

Possible increased risk of hemorrhagic events (see Hemorrhage under Cautions)1

Digoxin

Increased peak plasma concentration and AUC of digoxin by 34 and 11%, respectively1 7

Diltiazem

Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 151 and 157%, respectively1 7

Reduce zanubrutinib once- or twice-daily dosage to 80 mg twice daily1 7

Efavirenz

Simulations suggest zanubrutinib peak plasma concentration and AUC decreased by 58 and 60%, respectively1

Avoid concomitant use1

Histamine H2-receptor antagonists

No clinically important effect on pharmacokinetics of zanubrutinib1

Macrolides (clarithromycin, erythromycin)

Clarithromycin: Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 175 and 183%, respectively1 7

Erythromycin: Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 284 and 317%, respectively1 7

Potent CYP3A inhibitors (e.g., clarithromycin):7 Reduce zanubrutinib once- or twice-daily dosage to 80 mg once daily1

Moderate CYP3A inhibitors (e.g., erythromycin7 ): Reduce zanubrutinib once- or twice-daily dosage to 80 mg twice daily1

Midazolam

Decreased midazolam peak plasma concentration and AUC by 30 and 47%, respectively.1 7

Proton-pump Inhibitors

No clinically important effects on pharmacokinetics of zanubrutinib1

Zanubrutinib decreased omeprazole (CYP2C19 substrate) peak plasma concentration and AUC by 20 and 36%, respectively1

Rosiglitazone

Simulations suggest no clinically important effect on rosiglitazone pharmacokinetics1

Rosuvastatin

No clinically important effect on rosuvastatin pharmacokinetics1 7

Zanubrutinib Pharmacokinetics

Absorption

Bioavailability

Systemic exposure increases in a dose proportional manner over a dosage range of 40–320 mg.1 3 Minimal accumulation with repeated dosing.1 3

Peak plasma concentration attained in 2 hours.1 3

Duration

Median steady-state binding of drug to BTK (BTK occupancy) in peripheral blood mononuclear cells maintained at 100% over 24 hours.1 7 10

Median steady-state binding of drug to BTK in lymph nodes is 94–100%.1 7 10

Food

High-fat meal did not substantially alter AUC or peak plasma concentration.1 7

Special Populations

Mild hepatic impairment (Child-Pugh class A): Total or unbound AUC increased by 11 or 23%, respectively.1 7

Moderate hepatic impairment (Child-Pugh class B): Total or unbound AUC increased by 21 or 43%, respectively.1 7

Severe hepatic impairment (Child-Pugh class C): Total or unbound AUC increased by 60 or 194%, respectively.1 7

Mild or moderate renal impairment (Clcr ≥30 mL/minute): Pharmacokinetics not substantially affected.1

Severe renal impairment (Clcr <30 mL/minute) or dialysis: Limited data.1

Distribution

Extent

Not known whether zanubrutinib or its metabolites are distributed into milk.1

Plasma Protein Binding

Approximately 94%.1 Blood to plasma ratio is 0.7–0.8.1

Elimination

Metabolism

Metabolized principally by CYP3A.1

Elimination Route

Eliminated in feces (87%; 38% as unchanged drug) and urine (8%; <1% as unchanged drug).1

Half-life

Mean half-life: Approximately 2–4 hours.1

Special Populations

Age (19–90 years), sex, race, or body weight (36–140 kg) do not substantially affect pharmacokinetics.1

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Selectively and irreversibly inhibits BTK, resulting in inhibition of downstream effector activity within the B-cell antigen receptor (BCR) signaling pathway.1 2 3 4 8 9 15 17 18

  • Inhibits proliferation of malignant B cells and reduces tumor growth.1 8

  • Inhibition of BTK reduces plasma concentration of cytokines and chemokines, which may lead to decreased cell adhesion and mobilization of cells from tissues.12 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.1 3 9 12

  • Does not target kinases other than BTK (i.e., epidermal growth factor receptor [EGFR], tyrosine kinase expressed in hepatocellular carcinoma [TEC], interleukin 2-inducible T-cell kinase [ITK]).3 4 10

Advice to Patients

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

  • Importance of advising patients to take zanubrutinib as directed by their clinician.1 If a dose is missed, importance of administering the missed dose as soon as it is remembered on the same day and resuming the regular dosing schedule the following day.1

  • Importance of advising patients to take zanubrutinib capsules orally with a glass of water; capsules should not be opened, broken, or chewed.1

  • Risk of 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 interruption of zanubrutinib therapy for major surgeries or procedures, including dental procedures, may be necessary.1

  • Risk of infection.1 Importance of informing clinician if signs or symptoms of infection occur (e.g., fever, chills, flu-like symptoms).1

  • Risk of myelosuppression and importance of periodic CBC monitoring.1

  • Risk of developing a second primary malignancy.1 Importance of advising patients to protect skin from sun exposure.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

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential and men who are partners of such women that they should use effective methods of contraception while receiving zanubrutinib and for ≥1 week after the last dose.1 Importance of women informing clinicians if they are or plan to become pregnant.1 Apprise of potential hazard to the fetus if used during pregnancy.1

  • Importance of advising women to avoid breast-feeding while receiving zanubrutinib and for ≥2 weeks after the last dose.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., anticoagulant or antiplatelet drugs) 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 zanubrutinib is restricted.6 (See Restricted Distribution under Dosage and Administration.)

Zanubrutinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

80 mg

Brukinsa

BeiGene

AHFS DI Essentials™. © Copyright 2021, Selected Revisions September 28, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. BeiGene USA. Brukinsa (zanubrutinib) gelatin-coated capsules prescribing information. San Mateo, CA; 2019 Nov.

2. Song Y, Zhou K, Zou D et al. Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma from a Phase 2 Trial . Blood. 2018; 132:148.

3. Tam CS, Trotman J, Opat S et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019; 134:851-9.

4. Wu, J, Liu, C, Tsui ST. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016; 9(1):1-7. http://www.ncbi.nlm.nih.gov/pubmed/27590878?dopt=AbstractPlus

5. 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

6. BeiGene USA. Brukinsa (zanubrutinib) Access To Brukinsa. From the BeiGene website. Accessed 2020 Feb 11. https://www.brukinsa.com/ordering-information-and-distribution-sheet.pdf

7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 213217Orig1s000: Multi-discipline review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/213217Orig1s000MultidisciplineR.pdf

8. Li CJ, Jiang C, Liu Y et al. Pleiotropic Action of Novel Bruton's Tyrosine Kinase Inhibitor BGB-3111 in Mantle Cell Lymphoma. Mol Cancer Ther. 2019; 18:267-77. http://www.ncbi.nlm.nih.gov/pubmed/30413649?dopt=AbstractPlus

9. Bond, DA, Alinari, L, Maddocks, K. Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions. Clin Adv Hematol Oncol. 2019; 17:223-33. http://www.ncbi.nlm.nih.gov/pubmed/31188814?dopt=AbstractPlus

10. Tam CS, LeBlond V, Novotny W et al. A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia. Future Oncol. 2018; 14:2229-37. http://www.ncbi.nlm.nih.gov/pubmed/31188814?dopt=AbstractPlus

12. Chang, BY, Francesco M, De Rooij MF et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013; 122:2414-24. http://www.ncbi.nlm.nih.gov/pubmed/23940282?dopt=AbstractPlus

13. AstraZeneca Pharmaceuticals LP. Calquence (acalabrutinib) gelatin-coated capsules prescribing information. Wilmington, DE; 2019 Nov.

14. Advani RH, Buggy JJ, Sharman JP et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013; 31:88-94. http://www.ncbi.nlm.nih.gov/pubmed/23045577?dopt=AbstractPlus

15. Dasmahapatra G, Patel H, Dent P et al. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol. 2013; 161:43-56. http://www.ncbi.nlm.nih.gov/pubmed/23360303?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3739300&blobtype=pdf

16. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012; 120:1175-84. http://www.ncbi.nlm.nih.gov/pubmed/22715122?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3418714&blobtype=pdf

17. Chavez JC, Sahakian E, Pinilla-Ibarz J. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia. Core Evid. 2013; 8:37-45. http://www.ncbi.nlm.nih.gov/pubmed/23717217?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3662532&blobtype=pdf

18. Dias AL, Jain D. Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton's Tyrosine Kinase Inhibition. Cardiovasc Hematol Agents Med Chem. 2013; 11:265-71. http://www.ncbi.nlm.nih.gov/pubmed/24433470?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4010045&blobtype=pdf

Frequently Asked Questions