Zanubrutinib (Monograph)

Brand name: Brukinsa
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

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

Uses for Zanubrutinib

Mantle Cell Lymphoma

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

This indication is approved under accelerated approval based on overall response rate. Continued FDA approval may be contingent on verification and description of clinical benefit in additional trials.

Waldenström's Macroglobulinemia

Treatment of Waldenström’s macroglobulinemia in adults; designated an orphan drug by FDA for this cancer.

Marginal Zone Lymphoma

Treatment of relapsed or refractory marginal zone lymphoma in adults who have received at least one prior anti-CD20-based regimen; designated an orphan drug by FDA for this cancer.

Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); designated an orphan drug by FDA for the treatment of CLL.

Follicular Lymphoma

Treatment of adults with relapsed or refractory follicular lymphoma, in combination with obinutuzumab, after ≥2 lines of systemic therapy; designated an orphan drug by FDA for this cancer.

This indication is approved under accelerated approval based on overall response rate and durability of response. Continued FDA approval may be contingent on verification and description of clinical benefit in additional trials.

Zanubrutinib Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential.
Evaluate bilirubin and transaminases at baseline.

Patient Monitoring

Monitor for signs and symptoms of bleeding. Discontinue zanubrutinib if intracranial hemorrhage occurs.
Monitor for fever and other signs and symptoms of infection.
Monitor CBCs regularly during therapy. Treatment modifications or administration of growth factor or transfusions may be warranted.
Monitor for development of second primary malignancies.
Monitor for signs and symptoms of serious cardiac arrhythmias.
Monitor bilirubin and transaminases during therapy; in patients who develop abnormal liver tests, monitor more frequently for liver test abnormalities and clinical manifestations of hepatotoxicity.

Premedication and Prophylaxis

Consider prophylaxis for herpes simplex virus (HSV) infection, Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP), and other infections according to current standards of care in patients who are at an increased risk for infections.

Other General Considerations

Manufacturer recommends that patients use sun protection during zanubrutinib therapy.
Based on a risk-benefit assessment, consider withholding zanubrutinib for 3–7 days before and after surgical procedures, depending on the surgery type and associated risk of bleeding.

Administration

Oral Administration

May be given as monotherapy or in combination with obinutuzumab dependent upon indication for use.

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

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

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

Dosage

Adults

Mantle Cell Lymphoma

Oral

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

Waldenström's Macroglobulinemia

Oral

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

Marginal Zone Lymphoma

Oral

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

Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Oral

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

Follicular Lymphoma

Oral

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

Dosage Modification for Toxicity

Oral

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

No dosage adjustment necessary in patients with asymptomatic lymphocytosis with CLL and mantle cell lymphoma.

Refer to obinutuzumab prescribing information for management of obinutuzumab-related adverse reactions.

Table 1: Recommended Dosage Modifications for Zanubrutinib Toxicity1
Toxicity Occurrence	Dosage Modification after Recovery from Toxicity Initial Dosage = 160 mg twice daily	Dosage Modification after Recovery from Toxicity 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

Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Recommended dosage modifications of zanubrutinib with concomitant use of CYP3A inhibitors or inducers are provided in Table 2. Modify or interrupt the dosage of zanubrutinib as recommended for adverse reactions. In addition, after discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume the previous zanubrutinib dosage.

Table 2. Dosage Modifications for Concomitant Use of Zanubrutinib with CYP3A Inhibitors or Inducers.1
Concomitant Drug	Recommended Zanubrutinib Dosage Initial Dosage = 160 mg twice daily or 320 mg once daily
Clarithromycin 250 mg twice daily	80 mg twice daily
Clarithromycin 500 mg twice daily	80 mg once daily
Posaconazole suspension 100 mg once daily	80 mg twice daily
Posaconazole suspension dosage >100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole 300 mg IV once daily	80 mg once daily
Other strong CYP3A inhibitor	80 mg once daily
Moderate CYP3A inhibitor	80 mg twice daily
Strong CYP3A inducer	Avoid concomitant use
Moderate CYP3A inducer	Avoid concomitant use; if inducers can not be avoided, increase zanubrutinib dosage to 320 mg twice daily

Special Populations

Hepatic Impairment

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

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

Renal Impairment

Patients receiving dialysis: monitor for signs of toxicity.

Mild to severe renal impairment (Cl_cr ≥15 mL/minute): No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Zanubrutinib

Contraindications

None.

Warnings/Precautions

Hemorrhage

Serious hemorrhagic events (i.e., intracranial or GI hemorrhage, hematuria, hemothorax), sometimes fatal, reported in zanubrutinib-treated patients with hematologic malignancies. Hemorrhagic events of any grade, excluding purpura and petechiae, reported in 32% of patients receiving zanubrutinib.

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

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).

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

Infectious Complications

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

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

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

Hematologic Effects

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

Monitor CBCs during therapy. If hematologic toxicity occurs, interruption of therapy followed by dosage reduction may be necessary. Initiate appropriate therapeutic measures (e.g., hematopoietic growth factor or transfusion) as necessary.

Development of Second Primary Malignancy

Second primary malignancies, including non-skin carcinomas, reported in patients with hematologic malignancies receiving single-agent zanubrutinib. Non-melanoma skin cancer most frequently reported second primary malignancy; other reported malignancies include malignant solid tumors, melanoma, or hematologic malignancies. Monitor patients for development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias reported. Increased risk in those with cardiac risk factors, hypertension, or acute infection.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort) and institute appropriate management.

Hepatotoxicity

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury, reported.

Evaluate bilirubin and transaminases at baseline and during therapy. In patients who develop abnormal liver tests, monitor more frequently for liver test abnormalities and clinical manifestations of hepatotoxicity. Withhold therapy if drug-induced liver injury suspected and discontinue therapy upon confirmation.

Fetal/Neonatal Morbidity and Mortality

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

Avoid pregnancy during therapy. Women of reproductive potential should use effective contraceptive methods during therapy and for 1 week after the last dose. Men should avoid fathering a child during and for 1 week after the last dose. If used during pregnancy, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

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.

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

Females and Males of Reproductive Potential

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

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No clinically important differences in efficacy compared with younger adults. Increased rates of grade 3 or higher adverse reactions and serious adverse reactions observed in geriatric patients.

Hepatic Impairment

Increased systemic exposure in patients with hepatic impairment.

Dosage adjustment required in patients with severe hepatic impairment.

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

Renal Impairment

Mild, moderate, or severe renal impairment (Cl_cr ≥15 mL/minute) does not substantially alter pharmacokinetics of zanubrutinib.

Limited data in patients undergoing dialysis; monitor for toxicity.

Common Adverse Effects

Adverse effects (≥30%): decreased neutrophil count, decreased platelet count, upper respiratory tract infection, hemorrhage, musculoskeletal pain.

Drug Interactions

Metabolized principally by CYP3A.

In vitro, zanubrutinib induces CYP2B6 and CYP2C8. Weak inducer of CYP3A4 and 2C19 in vivo.

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.

Drugs Affecting Hepatic Microsomal Enzymes

Strong or moderate inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, zanubrutinib. If concomitant use is necessary, reduce zanubrutinib dosage (see Table 2).

Strong or moderate inducers of CYP3A: Possible decreased systemic exposure to, and decreased therapeutic efficacy of, zanubrutinib. Avoid concomitant use. If concomitant use of a moderate CYP3A inducer is necessary, increase the dosage of zanubrutinib to 320 mg twice daily (see Table 2).

Drugs Metabolized by Hepatic Microsomal Enzymes

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

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

Substrates of Efflux Transport Systems

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

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

Drugs Affecting Gastric Acidity

No clinically meaningful effect on pharmacokinetics of zanubrutinib.

Specific Drugs

Drug	Interaction	Comments
Anticoagulants	Possible increased risk of hemorrhagic events No clinically important effect on pharmacokinetics of warfarin
Antifungals, azole (e.g., fluconazole, itraconazole)	Possible increased peak plasma concentration and systemic exposure of zanubrutinib Itraconazole: Increased zanubrutinib peak plasma concentration and AUC by 157 and 278%, respectively Fluconazole: Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 179–270 and 177–284%, respectively	Strong CYP3A inhibitors (e.g., itraconazole): Reduce zanubrutinib dosage Moderate CYP3A inhibitors (e.g., fluconazole): Reduce zanubrutinib dosage
Antimycobacterials, rifamycins (e.g., rifampin)	Possible decreased peak plasma concentration and AUC of zanubrutinib Rifampin decreased zanubrutinib peak plasma concentration and AUC by 92 and 93%, respectively	Avoid concomitant use
Antiplatelet agents	Possible increased risk of hemorrhagic events
Digoxin	Increased peak plasma concentration and AUC of digoxin by 34 and 11%, respectively
Diltiazem	Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 151 and 157%, respectively	Reduce zanubrutinib dosage
Efavirenz	Simulations suggest zanubrutinib peak plasma concentration and AUC decreased by 58 and 60%, respectively	Avoid concomitant use
Histamine H₂-receptor antagonists	No clinically important effect on pharmacokinetics of zanubrutinib
Macrolides (clarithromycin, erythromycin)	Clarithromycin: Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 175 and 183%, respectively Erythromycin: Simulations suggest zanubrutinib peak plasma concentration and AUC increased by 284 and 317%, respectively	Strong CYP3A inhibitors (e.g., clarithromycin): Reduce zanubrutinib dosage Moderate CYP3A inhibitors (e.g., erythromycin ): Reduce zanubrutinib dosage
Midazolam	Decreased midazolam peak plasma concentration and AUC by 30 and 47%, respectively.
Proton-pump Inhibitors	No clinically important effects on pharmacokinetics of zanubrutinib Zanubrutinib decreased omeprazole (CYP2C19 substrate) peak plasma concentration and AUC by 20 and 36%, respectively
Rosuvastatin	No clinically important effect on rosuvastatin pharmacokinetics

Zanubrutinib Pharmacokinetics

Absorption

Bioavailability

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

Peak plasma concentration attained in 2 hours.

Duration

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

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

Food

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

Special Populations

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

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

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

Mild, moderate, or severe renal impairment (Cl_cr ≥15 mL/minute): Pharmacokinetics not substantially affected.

Dialysis: Limited data.

Distribution

Extent

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

Plasma Protein Binding

Approximately 94%. Blood to plasma ratio is 0.7–0.8.

Elimination

Metabolism

Metabolized principally by CYP3A.

Elimination Route

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

Half-life

Mean half-life: Approximately 2–4 hours.

Special Populations

Age (19–90 years), sex, race, body weight (36–144 kg), or renal impairment do not substantially affect pharmacokinetics.

Stability

Storage

Oral

Capsules

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

Actions

Selectively and irreversibly inhibits BTK, resulting in inhibition of downstream effector activity within the B-cell antigen receptor (BCR) signaling pathway.
Inhibits proliferation of malignant B cells and reduces tumor growth.
Inhibition of BTK reduces plasma concentration of cytokines and chemokines, which may lead to decreased cell adhesion and mobilization of cells from tissues. 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.
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]).

Advice to Patients

Instruct patients to read the manufacturer's patient information.
Advise patients to take zanubrutinib as directed by their clinician. If a dose is missed, stress 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.
Advise patients to take zanubrutinib capsules orally with a glass of water, with or without food; capsules should not be opened, broken, or chewed.
Risk of hemorrhage. Stress importance of informing clinician if signs or symptoms of severe bleeding occur (e.g., blood in stool or urine; unexpected, prolonged, or uncontrolled bleeding). Inform patients that interruption of zanubrutinib therapy for major surgeries or procedures, including dental procedures, may be necessary.
Risk of infection. Stress importance of informing clinician if signs or symptoms of infection occur (e.g., fever, chills, flu-like symptoms).
Risk of developing a second primary malignancy. Advise patients to protect skin from sun exposure and monitor for the development of other cancers
Risk of serious cardiac arrhythmias. Stress importance of informing clinician if palpitations, lightheadedness, dizziness, fainting, shortness of breath, or chest discomfort occurs.
Risk of hepatotoxicity. Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may occur. Advise patients to contact their clinician immediately if they experience abdominal discomfort, dark urine, or jaundice.
Risk of fetal harm. Advise women of reproductive 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. Stress importance of women informing clinicians if they are or plan to become pregnant. Apprise of potential hazard to the fetus if used during pregnancy.
Advise women to avoid breast-feeding while receiving zanubrutinib and for 2 weeks after the last dose.
Stress 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.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.

Zanubrutinib is available only from designated specialty pharmacies and distributors. The manufacturer should be contacted for additional information.