Brukinsa (Zanubrutinib)
zanubrutinib
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| CLL or SLL | Adults | Monotherapy | FDA Approved |
| Waldenström macroglobulinemia (WM) | Adults | Monotherapy | FDA Approved |
| Previously treated MCL | Adults (≥1 prior therapy) | Monotherapy | Accelerated Approval |
| Relapsed/refractory MZL | Adults (≥1 anti-CD20 regimen) | Monotherapy | Accelerated Approval |
| Relapsed/refractory FL | Adults (≥2 lines of systemic therapy) | Combination with obinutuzumab | Accelerated Approval |
Zanubrutinib is the most broadly approved BTK inhibitor in the United States, spanning five haematologic malignancy indications. Its design emphasises maximising BTK receptor occupancy across disease-relevant tissues while minimising off-target kinase inhibition. In the ALPINE trial, zanubrutinib demonstrated superior PFS compared with ibrutinib in relapsed/refractory CLL/SLL, and in ASPEN it showed a favourable cardiovascular safety profile versus ibrutinib in WM. Zanubrutinib is the current US market share leader for BTK inhibitors in new CLL patient starts across all lines of therapy. The MCL, MZL, and FL indications remain under accelerated approval pending confirmatory trial data.
Central nervous system lymphoma: Early clinical data and case series suggest BTK inhibitor activity in CNS lymphoma given zanubrutinib’s tissue penetration. Evidence quality: Low (early-phase/case series).
Chronic GVHD: Not FDA-approved for cGVHD (ibrutinib holds this indication), though BTK inhibition has mechanistic rationale. Evidence quality: Very low (extrapolation from class).
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CLL/SLL — any line, monotherapy | 160 mg BID or 320 mg QD | 160 mg BID or 320 mg QD | 320 mg/day | Continue until progression or intolerance Flexible dosing schedule; take with or without food |
| Waldenström macroglobulinemia — monotherapy | 160 mg BID or 320 mg QD | 160 mg BID or 320 mg QD | 320 mg/day | Continue until progression or intolerance ASPEN trial used 160 mg BID; either schedule acceptable |
| Previously treated MCL — monotherapy | 160 mg BID or 320 mg QD | 160 mg BID or 320 mg QD | 320 mg/day | After ≥1 prior therapy; accelerated approval Asymptomatic lymphocytosis is expected and not a reason to discontinue |
| R/R MZL — monotherapy | 160 mg BID or 320 mg QD | 160 mg BID or 320 mg QD | 320 mg/day | After ≥1 anti-CD20 regimen Accelerated approval indication |
| R/R FL — with obinutuzumab | 160 mg BID | 160 mg BID | 320 mg/day | After ≥2 systemic therapy lines; obinutuzumab 1000 mg IV per schedule ROSEWOOD trial protocol; zanubrutinib continues beyond obinutuzumab |
| Severe hepatic impairment | 80 mg BID | 80 mg BID | 160 mg/day | 50% dose reduction AUC 1.6-fold higher (total), 2.9-fold higher (unbound) vs healthy controls |
Dose Modifications for CYP3A Interactions
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| With moderate CYP3A inhibitor | 80 mg BID | 80 mg BID | 160 mg/day | Resume standard dose after inhibitor cleared |
| With strong CYP3A inhibitor (most agents) | 80 mg QD | 80 mg QD | 80 mg/day | Applies to most strong CYP3A4 inhibitors Specific adjustments for posaconazole and clarithromycin — see PI Table 1 |
| With unavoidable moderate CYP3A inducer | 320 mg BID | 320 mg BID | 640 mg/day | Doubled dose to compensate for reduced exposure Avoid strong CYP3A inducers entirely |
Zanubrutinib is the only approved BTK inhibitor offering a choice between twice-daily (160 mg BID) and once-daily (320 mg QD) dosing. Both schedules achieve comparable daily AUC exposure and sustained BTK occupancy. The BID schedule provides more consistent plasma levels throughout the day, while QD dosing may improve adherence for some patients. Unlike acalabrutinib capsules, zanubrutinib absorption is not significantly affected by proton pump inhibitors, simplifying management for patients on acid-reducing therapy.
For haematologic toxicities (Grade 3/4 febrile neutropenia, sustained Grade 4 cytopenias, or significant thrombocytopenic bleeding): first occurrence — interrupt then resume at full dose; second — resume at 80 mg BID or 160 mg QD; third — resume at 80 mg QD; fourth — discontinue permanently. Non-haematologic Grade 3/4 toxicities follow the same stepwise pattern.
Pharmacology
Mechanism of Action
Zanubrutinib is a potent, second-generation covalent inhibitor of Bruton tyrosine kinase (BTK) designed to maximise BTK occupancy in disease-relevant tissues while minimising off-target kinase inhibition. It forms a covalent bond with cysteine-481 in the BTK active site, irreversibly blocking BTK enzymatic activity. This disrupts B-cell receptor signalling cascades essential for malignant B-cell proliferation, survival, adhesion, and tissue homing. Compared with ibrutinib, zanubrutinib demonstrates significantly less inhibition of EGFR, ITK, TEC, and Src family kinases at therapeutic concentrations, which accounts for its improved cardiovascular safety profile — particularly its lower rates of atrial fibrillation and hypertension. In the head-to-head ALPINE trial against ibrutinib in relapsed/refractory CLL, zanubrutinib showed both superior efficacy (PFS) and lower cardiac toxicity, validating the clinical benefit of its selectivity profile. Zanubrutinib produces the expected BTK-inhibitor-class redistribution lymphocytosis in CLL and MCL, which should not be mistaken for disease progression.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; median Tmax ~2 h; estimated oral bioavailability ~15% (PBPK); dose-proportional increase in AUC from 40–320 mg; food does not clinically affect exposure | No food restrictions; PPIs do not significantly affect absorption (key advantage over acalabrutinib capsules) |
| Distribution | Apparent Vss ~881 L; protein binding 91–95%; blood-to-plasma ratio 0.7–0.8 | Very high apparent volume indicates extensive tissue distribution; lower protein binding than ibrutinib or acalabrutinib may contribute to broader tissue exposure |
| Metabolism | Hepatic primarily via CYP3A4; no major active circulating metabolites; also induces CYP2B6 and CYP2C8 | Strong CYP3A4 dependence; unlike acalabrutinib, no pharmacologically active metabolite with independent half-life |
| Elimination | t½ 2–4 h; limited accumulation at steady state; likely substrate of P-glycoprotein | Short half-life offset by irreversible BTK binding; BID dosing maintains continuous BTK occupancy; P-gp substrate status relevant for interaction assessment |
Side Effects
Adverse reaction data below are derived from the pooled safety population of 1,729 patients with haematologic malignancies treated with zanubrutinib in 11 clinical trials (FDA PI, revised January 2025). The median duration of exposure was 27.6 months, with 78% exposed for at least 12 months and 60% for at least 24 months.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Neutrophil count decreased (lab) | 51% | All grades; Grade 3/4 in 21%; Grade 4 in 10%; monitor CBC regularly |
| Platelet count decreased (lab) | 41% | All grades; Grade 3/4 in 8%; Grade 4 in 2.5% |
| Upper respiratory tract infection | 27–44% | Pooled 38%; includes nasopharyngitis, sinusitis; Grade 3+ rare (≤3%) |
| Haemorrhage (any, excl. purpura/petechiae) | 32% | Any-grade bleeding events; coadministration with antithrombotics increases risk |
| Musculoskeletal pain | 14–45% | Pooled 31%; includes arthralgia, back pain, myalgia; Grade 3+ in 0.6–9% |
| Haemoglobin decreased (lab) | 20–31% | All grades; Grade 3/4 in 2.5–7% |
| Rash | 11–36% | Includes dermatitis; usually Grade 1–2 |
| Bruising | 14–26% | Contusion, ecchymosis; cosmetic; lower rate than ibrutinib |
| Diarrhea | 14–25% | Usually Grade 1–2; loperamide for symptom control |
| Pneumonia | 10–20% | Includes COVID-19 pneumonia and LRTI; Grade 3+ in 4–13%; fatal cases reported |
| Fatigue | 13–31% | Includes asthenia and lethargy; usually Grade 1–2 |
| Hypertension | 11–19% | Grade 3+ in 7–14%; lower than ibrutinib in ASPEN (14% vs 19%) and ALPINE (19% vs 20%) |
| Cough | 10–18% | Usually Grade 1; rarely requires intervention |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Atrial fibrillation / flutter | 4.4% | Grade 3+ in 1.9%; significantly lower than ibrutinib in head-to-head trials |
| Headache | 4–18% | Lower incidence than acalabrutinib (35%) |
| Urinary tract infection | 7–11% | Grade 3+ uncommon |
| Nausea | 10–18% | Grade 3 rare |
| Constipation | 10–18% | Grade 3 rare |
| Peripheral oedema | 4.6–12% | Lower rate than ibrutinib (20% vs ASPEN data) |
| Muscle spasms | 10% | Significantly lower than ibrutinib (10% vs 28% in ASPEN) |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Grade 3+ haemorrhage (incl. CNS) | 3.8% | Any time during treatment | Discontinue if intracranial haemorrhage of any grade; fatal in 0.2%; withhold 3–7 days pre/post-surgery |
| Grade 3+ infections | 26% | Throughout treatment | Pneumonia most common (7.9%); fatal infections in 3.2%; HBV reactivation risk; consider HSV, PJP, and antifungal prophylaxis |
| Grade 3/4 cytopenias | Neutropenia 21%; thrombocytopenia 8%; anaemia 8% | First months; ongoing | Monitor CBC regularly; interrupt/reduce/discontinue per dose modification table; G-CSF or transfusion as needed |
| Second primary malignancies | 14% | Cumulative over treatment duration | NMSC 8%, other solid tumours 7%, melanoma 1%; sun protection; annual dermatological review |
| AF / flutter (Grade 3+) | 1.9% | Variable | ECG; cardiology referral; rate/rhythm control; dose modification per PI |
| Ventricular arrhythmias (Grade 3+) | 0.3% | Variable | Urgent evaluation; consider permanent discontinuation |
| Drug-induced liver injury (DILI) | Rare (class-wide, postmarketing) | Variable | Monitor LFTs; withhold if suspected; permanently discontinue if confirmed |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Pneumonia / respiratory infections | Leading cause (ALPINE) | Includes COVID-19 pneumonia; dose modification required in ≥5% of patients |
| Second primary malignancies | Leading cause (SEQUOIA) | NMSC most frequent; annual skin examination recommended |
| MCL trials: 7% overall | 7% | Pneumonia most frequent cause (3.4%) |
In the ALPINE trial (R/R CLL), zanubrutinib demonstrated significantly lower rates of atrial fibrillation (4.6% vs ibrutinib not reported in this context, but class difference is established) and hypertension versus ibrutinib. In the ASPEN trial (WM), all-grade AF/flutter was lower with zanubrutinib, and muscle spasms were markedly less frequent (10% vs 28%). This cardiovascular safety profile is a key differentiator for zanubrutinib within the BTK inhibitor class.
Drug Interactions
Zanubrutinib is primarily metabolised by CYP3A4. Co-administration with the strong CYP3A4 inducer rifampin decreased zanubrutinib Cmax by 12.6-fold and AUC by 13.5-fold. Unlike acalabrutinib capsules, zanubrutinib absorption is not significantly affected by proton pump inhibitors, providing a practical advantage for patients requiring acid suppression. Zanubrutinib is likely a P-glycoprotein substrate and an inducer of CYP2B6 and CYP2C8.
Monitoring
- Complete Blood CountRegularly during treatment
RoutineGrade 3/4 cytopenias: neutropenia 21%, thrombocytopenia 8%, anaemia 8%. Grade 4 neutropenia in 10%, Grade 4 thrombocytopenia in 2.5%. Interrupt, reduce, or discontinue per dose modification guidelines; G-CSF or transfusion as needed. - Hepatic FunctionBaseline, then periodically
RoutineEvaluate bilirubin and transaminases at baseline and throughout treatment. DILI has been reported with BTK inhibitors including zanubrutinib. If liver test abnormalities develop, increase monitoring frequency. Withhold if DILI suspected; discontinue if confirmed. - Cardiac RhythmBaseline + as indicated
RoutineAF/flutter in 4.4%, Grade 3+ in 1.9%. Ventricular arrhythmias Grade 3+ in 0.3%. Evaluate symptoms (palpitations, syncope, dyspnoea) with ECG. Higher risk with cardiac risk factors, hypertension, and acute infections. - Bleeding AssessmentEach visit; ongoing
RoutineGrade 3+ haemorrhage in 3.8%, fatal in 0.2%. Discontinue immediately for intracranial haemorrhage of any grade. Withhold 3–7 days pre/post-surgery. Assess concurrent anticoagulant/antiplatelet use. - Infection SurveillanceEach visit; ongoing
RoutineGrade 3+ infections in 26%; fatal infections in 3.2%. Pneumonia most common (7.9%). HBV reactivation reported — screen before initiation. Consider HSV, PJP, and antifungal prophylaxis per standard of care. - Skin ExaminationBaseline, then annually
RoutineSecond primary malignancies in 14%; NMSC in 8%, other solid tumours in 7%, melanoma in 1%. Advise sun protection. Annual dermatological review recommended. - Blood PressureEach visit
RoutineHypertension reported in 11–19%; Grade 3+ in 7–14%. Initiate or adjust antihypertensives as needed. - Pregnancy StatusBefore initiation
Trigger-basedZanubrutinib causes fetal harm including cardiac malformations in rats at 5x human exposure. Contraception required during treatment and for 1 week after last dose (both men and women).
Contraindications & Cautions
Absolute Contraindications
- Pregnancy: Zanubrutinib caused cardiac malformations (2- or 3-chambered hearts) in rats at all dose levels tested, including at exposures as low as 5 times the human dose. Must not be used in pregnant women.
Relative Contraindications (Specialist Input Recommended)
- Active intracranial haemorrhage or history of CNS bleeding: The PI mandates permanent discontinuation for intracranial haemorrhage of any grade.
- Concomitant strong CYP3A4 inducer therapy: 13.5-fold reduction in zanubrutinib AUC with rifampin — likely renders treatment ineffective. Avoid combination.
- Active uncontrolled hepatitis B: HBV reactivation has been reported. Screen and manage before initiation.
Use with Caution
- Severe hepatic impairment: Reduce dose to 80 mg BID (unbound AUC 2.9-fold higher than healthy controls). Monitor more closely for adverse reactions.
- Patients on anticoagulants or antiplatelet agents: Additive bleeding risk. Avoid warfarin if possible; DOACs preferred.
- Elderly (≥65 years): 59% of pooled safety population; numerically higher rates of Grade 3+ adverse reactions and serious adverse reactions.
- Patients with cardiac risk factors: AF/flutter risk of 4.4%; higher in patients with hypertension, prior arrhythmias, and acute infection.
- Planned surgery within 3–7 days: Withhold zanubrutinib peri-operatively.
Serious cardiac arrhythmias have occurred with zanubrutinib. Atrial fibrillation and atrial flutter were reported in 4.4% of patients, including Grade 3 or higher cases in 1.9%. Grade 3 or higher ventricular arrhythmias were reported in 0.3%. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Monitor for arrhythmia symptoms and manage appropriately.
Severe, life-threatening, and potentially fatal cases of DILI have been reported with BTK inhibitors including zanubrutinib. Monitor hepatic function at baseline and throughout treatment. Withhold if suspected; permanently discontinue if confirmed.
Patient Counselling
Purpose of Therapy
Zanubrutinib is a targeted oral therapy that blocks a protein called BTK, which cancer cells need to grow and survive. It is not traditional chemotherapy. You will take it either once or twice daily as a continuous treatment to control your disease. A temporary increase in white blood cell count early in treatment is expected and does not indicate treatment failure.
How to Take
Take zanubrutinib as prescribed — either 160 mg twice daily (approximately 12 hours apart) or 320 mg once daily. If using capsules, this means two 80 mg capsules per dose (BID) or four capsules once daily. If using tablets, this means one 160 mg tablet per dose (BID) or two tablets once daily. Swallow capsules whole with water; do not open, break, or chew them. Tablets are scored and may be split if prescribed by your doctor. You can take zanubrutinib with or without food. If you miss a dose, take it as soon as possible on the same day and return to your normal schedule the next day.
Sources
- Brukinsa (zanubrutinib) capsules prescribing information. BeiGene USA, Inc. Revised January 2025. FDA LabelPrimary source for all dosing, indications, adverse reactions, warnings, and pharmacokinetic data in this monograph.
- Brukinsa Summary of Product Characteristics (SmPC). European Medicines Agency. EMAEuropean regulatory reference providing additional PK and safety data.
- Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319–332. doi:10.1056/NEJMoa2211582ALPINE trial; pivotal head-to-head Phase 3 study demonstrating superior PFS of zanubrutinib over ibrutinib in R/R CLL.
- Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038–2050. doi:10.1182/blood.2020006844ASPEN trial; Phase 3 comparison of zanubrutinib vs ibrutinib in WM showing comparable efficacy with improved tolerability.
- Tam CS, Robak T, Ghia P, et al. Zanubrutinib monotherapy for patients with treatment-naïve chronic lymphocytic leukemia and 17p deletion. Blood Adv. 2021;5(23):5032–5042. doi:10.1182/bloodadvances.2021005394SEQUOIA Cohort 2; single-arm data in treatment-naïve CLL with del(17p).
- Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton’s tyrosine kinase. Clin Cancer Res. 2020;26(16):4216–4224. doi:10.1158/1078-0432.CCR-19-3703BGB-3111-206 MCL trial supporting accelerated approval; demonstrated 84% ORR in previously treated MCL.
- Zinzani PL, Mayer J, Flowers CR, et al. ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2023;41(33):5107–5117. doi:10.1200/JCO.23.00175ROSEWOOD trial; basis for accelerated FL approval showing 69% ORR with zanubrutinib-obinutuzumab combination.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2026. NCCNPositions zanubrutinib as a preferred BTK inhibitor option for CLL/SLL across treatment lines.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 2.2025. NCCNTreatment algorithm including zanubrutinib for MCL, MZL, and FL.
- Guo Y, Liu Y, Hu N, et al. Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton’s tyrosine kinase. J Med Chem. 2019;62(17):7923–7940. doi:10.1021/acs.jmedchem.9b00687Discovery and preclinical characterisation of zanubrutinib demonstrating its selectivity advantage and in vivo potency.
- Ou YC, Liu L, Tariq B, et al. Population pharmacokinetic analysis of the BTK inhibitor zanubrutinib in healthy volunteers and patients with B-cell malignancies. Clin Transl Sci. 2021;14(2):764–772. doi:10.1111/cts.12948Population PK model characterising zanubrutinib absorption, distribution, and elimination; no clinically meaningful covariates identified.
- Ou YC, Preston RA, Marbury TC, et al. A phase 1, open-label, single-dose study of the pharmacokinetics of zanubrutinib in subjects with varying degrees of hepatic impairment. Leuk Lymphoma. 2020;61(6):1355–1363. doi:10.1080/10428194.2020.1719097Hepatic impairment PK study justifying the 80 mg BID dose reduction in severe hepatic impairment.
- Mu S, Tang Z, Novotny W, et al. Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib in Asian and non-Asian healthy subjects. Cancer Chemother Pharmacol. 2020;85(2):391–399. doi:10.1007/s00280-019-04015-yDDI study quantifying the 13.5-fold AUC reduction with rifampin and exposure increase with itraconazole.
- 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(11):851–859. doi:10.1182/blood.2019001160Phase 1 dose-finding study establishing the 160 mg BID and 320 mg QD dosing schedules with PK/PD data.