Zanubrutinib (Monograph)

Brand name: Brukinsa
Drug 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

Medically reviewed by Drugs.com on Sep 19, 2022. 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 patients who have received at least one prior therapy; designated an orphan drug by FDA for this cancer.

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

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. (See Infectious Complications under Cautions.)
Monitor CBCs during therapy.

Restricted Distribution

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

Administration

Oral Administration

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 the missed dose as soon as it is remembered on the same day. Take the next dose at the regularly scheduled time the following day.

Dosage

Adults

Mantle Cell Lymphoma

Oral

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

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

Special Populations

Hepatic Impairment

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

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

Renal Impairment

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

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

Geriatric Patients

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

Cautions for Zanubrutinib

Contraindications

Manufacturer states none known.

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, including purpura and petechiae, reported in 50% 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 hepatitis B virus (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. (See Dosage Modification for Toxicity under Dosage and Administration.) 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. Skin cancer (basal cell carcinoma and squamous cell carcinoma) most frequently reported second primary malignancy. (See Advice to Patients.)

Atrial Fibrillation and Flutter

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

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

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 of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm. (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.

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

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

Hepatic Impairment

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

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

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

Renal Impairment

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

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

Common Adverse Effects

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

Interactions for Zanubrutinib

Metabolized principally by CYP3A.

In vitro, zanubrutinib induces CYP2B6. 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

Potent inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, zanubrutinib. 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). When concomitant use of the potent CYP3A inhibitor is discontinued, return zanubrutinib dosage to dosage used prior to initiation of the potent CYP3A inhibitor.

Moderate inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, zanubrutinib. 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). When concomitant use of the moderate CYP3A inhibitor is discontinued, return zanubrutinib dosage to dosage used prior to initiation of the moderate CYP3A inhibitor.

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

Drugs Metabolized by Hepatic Microsomal Enzymes

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

Substrates of CYP2C9 or CYP2C8: 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 (see Hemorrhage under Cautions) 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	Potent CYP3A inhibitors (e.g., itraconazole): Reduce zanubrutinib once- or twice-daily dosage to 80 mg once daily Moderate CYP3A inhibitors (e.g., fluconazole): Reduce zanubrutinib once- or twice-daily dosage to 80 mg twice daily
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 (see Hemorrhage under Cautions)
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 once- or twice-daily dosage to 80 mg twice daily
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	Potent CYP3A inhibitors (e.g., clarithromycin): Reduce zanubrutinib once- or twice-daily dosage to 80 mg once daily Moderate CYP3A inhibitors (e.g., erythromycin ): Reduce zanubrutinib once- or twice-daily dosage to 80 mg twice daily
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
Rosiglitazone	Simulations suggest no clinically important effect on rosiglitazone pharmacokinetics
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 or moderate renal impairment (Cl_cr ≥30 mL/minute): Pharmacokinetics not substantially affected.

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

Distribution

Extent

Not known whether zanubrutinib or its metabolites are distributed into 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, or body weight (36–140 kg) do not substantially affect pharmacokinetics.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 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

Importance of instructing patients to read the manufacturer's patient information.
Importance of advising patients to take zanubrutinib as directed by their clinician. 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.
Importance of advising patients to take zanubrutinib capsules orally with a glass of water; capsules should not be opened, broken, or chewed.
Risk of hemorrhage. Importance of informing clinician if signs or symptoms of severe bleeding occur (e.g., blood in stool or urine; unexpected, prolonged, or uncontrolled bleeding). Importance of informing patients that interruption of zanubrutinib therapy for major surgeries or procedures, including dental procedures, may be necessary.
Risk of infection. Importance of informing clinician if signs or symptoms of infection occur (e.g., fever, chills, flu-like symptoms).
Risk of myelosuppression and importance of periodic CBC monitoring.
Risk of developing a second primary malignancy. Importance of advising patients to protect skin from sun exposure.
Risk of atrial fibrillation and flutter. Importance of informing clinician if palpitations, lightheadedness, dizziness, fainting, shortness of breath, or chest discomfort occurs.
Risk of fetal harm. 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. Importance of women informing clinicians if they are or plan to become pregnant. Apprise of potential hazard to the fetus if used during pregnancy.
Importance of advising women to avoid breast-feeding while receiving zanubrutinib and for ≥2 weeks after the last dose.
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.
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 zanubrutinib is restricted. (See Restricted Distribution under Dosage and Administration.)