Brukinsa Capsule
These highlights do not include all the information needed to use BRUKINSA safely and effectively. See full prescribing information for BRUKINSA. BRUKINSA® (zanubrutinib) capsules, for oral use BRUKINSA® (zanubrutinib) tablets, f…
Uses and indications
BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with: • Mantle cell lymphoma (MCL) who have received at least one prior therapy. (1.1) This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
• Waldenström's macroglobulinemia (WM). (1.2)
• Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti–CD20-based regimen. (1.3) This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
• Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). (1.4)
• Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy. (1.5) This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.1 Mantle Cell Lymphoma
BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.2 Waldenström's Macroglobulinemia
BRUKINSA is indicated for the treatment of adult patients with Waldenström's macroglobulinemia (WM) [see Clinical Studies (14.2)]. 1.3 Marginal Zone Lymphoma
BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti–CD20-based regimen.
This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.4 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
BRUKINSA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [see Clinical Studies (14.4)]. 1.5 Follicular Lymphoma
BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy.
This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Contraindications
None.
Side effects
Recommended dosage modifications of BRUKINSA for Grade 3 or higher adverse reactions are provided in Table 2.
| Adverse Reaction | Adverse Reaction Occurrence | Dosage Modification (Starting Dose: 160 mg twice daily or 320 mg once daily) |
|---|---|---|
| Hematological toxicities [see Warnings and Precautions (5.3)] | ||
| Grade 3 or Grade 4 febrile neutropenia Platelet count decreased to 25,000-50,000/mm3 with significant bleeding Neutrophil count decreased to <500/mm3 (lasting more than 10 consecutive days) Platelet count decreased to <25,000/mm3 (lasting more than 10 consecutive days) | First | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. |
| Second | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. | |
| Third | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. | |
| Fourth | Discontinue BRUKINSA | |
| Nonhematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)] | ||
| Severe or life-threatening nonhematological toxicitiesEvaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 nonhematological toxicity. | First | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. |
| Second | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. | |
| Third | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. | |
| Fourth | Discontinue BRUKINSA |
Asymptomatic lymphocytosis in CLL and MCL should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.
Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.
The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:
- Hemorrhage [see Warnings and Precautions (5.1)]
- Infections [see Warnings and Precautions (5.2)]
- Cytopenias [see Warnings and Precautions (5.3)]
- Second Primary Malignancies [see Warnings and Precautions (5.4)]
- Cardiac Arrhythmias [see Warnings and Precautions (5.5)]
- Hepatotoxicity, including DILI [see Warnings and Precautions (5.6)]
Precautions
• Hemorrhage
: Monitor for bleeding and manage appropriately. (5.1)
• Infections
: Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed. (5.2)
• Cytopenias
: Monitor complete blood counts during treatment. (5.3)
• Second Primary Malignancies
: Other malignancies have developed including skin cancers and non-skin carcinomas. Monitor and advise patients to use sun protection. (5.4)
• Cardiac Arrhythmias
: Monitor for signs and symptoms of arrhythmias and manage appropriately. (5.5)
• Hepatotoxicity, Including Drug-Induced Liver Injury
: Monitor hepatic function throughout treatment. (5.6)
• Embryo-Fetal Toxicity
: Can cause fetal harm. Advise women of the potential risk to a fetus and to use effective contraception. (5.7) 5.1 Hemorrhage
Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% of patients.
Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.
Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending upon the type of surgery and the risk of bleeding. 5.2 Infections
Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.
Consider prophylaxis for herpes simplex virus,
pneumocystis jirovecii
pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately. 5.3 Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%), and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA
[see Adverse Reactions (6.1)].
Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% of patients.
Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.4)]. Treat using growth factor or transfusions, as needed. 5.4 Second Primary Malignancies
Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies. 5.5 Cardiac Arrhythmias
Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% of patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.3% of patients.
Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately [see Dosage and Administration (2.4)], and consider the risks and benefits of continued BRUKINSA treatment. 5.6 Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including BRUKINSA.
Evaluate bilirubin and transaminases at baseline and throughout treatment with BRUKINSA. For patients who develop abnormal liver tests after BRUKINSA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold BRUKINSA. Upon confirmation of DILI, discontinue BRUKINSA. 5.7 Embryo-Fetal Toxicity
Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
Dosage
The recommended dosage of BRUKINSA for monotherapy or in combination with obinutuzumab is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.
The recommended dosage of BRUKINSA for patients with severe hepatic impairment (Child-Pugh class C) is 80 mg orally twice daily; no dosage modification is recommended for patients with mild or moderate hepatic impairment (Child-Pugh class A or B) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Recommended dosage modifications of BRUKINSA for drug interactions are provided in Table 1 [see Drug Interactions (7.1)].
| Coadministered Drug | Recommended BRUKINSA Dosage (Starting Dose: 160 mg twice daily or 320 mg once daily) |
|---|---|
| Clarithromycin 250 mg twice dailySince clarithromycin 250 mg twice daily acts as a moderate CYP3A inhibitor, it is recommended that patients be administered clarithromycin 250 mg twice daily with 80 mg BRUKINSA twice daily [see Clinical Pharmacology (12.3)]. | 80 mg twice dailyModify or interrupt zanubrutinib dose as recommended for adverse reactions [see Dosage and Administration (2.4)]. |
| Clarithromycin 500 mg twice daily | 80 mg once daily |
| Posaconazole suspension 100 mg once daily | 80 mg twice daily |
| Posaconazole suspension dosage higher than 100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole intravenous 300 mg 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 these inducers cannot be avoided, increase BRUKINSA dose to 320 mg twice daily. |
After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA [see Dosage and Administration (2.1, 2.2) and Drug Interactions (7.1)].
Recommended dosage modifications of BRUKINSA for Grade 3 or higher adverse reactions are provided in Table 2.
| Adverse Reaction | Adverse Reaction Occurrence | Dosage Modification (Starting Dose: 160 mg twice daily or 320 mg once daily) |
|---|---|---|
| Hematological toxicities [see Warnings and Precautions (5.3)] | ||
| Grade 3 or Grade 4 febrile neutropenia Platelet count decreased to 25,000-50,000/mm3 with significant bleeding Neutrophil count decreased to <500/mm3 (lasting more than 10 consecutive days) Platelet count decreased to <25,000/mm3 (lasting more than 10 consecutive days) | First | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. |
| Second | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. | |
| Third | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. | |
| Fourth | Discontinue BRUKINSA | |
| Nonhematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)] | ||
| Severe or life-threatening nonhematological toxicitiesEvaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 nonhematological toxicity. | First | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once daily. |
| Second | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once daily. | |
| Third | Interrupt BRUKINSA Once toxicity has resolved to Grade 1 or lower or baseline: Resume at 80 mg once daily. | |
| Fourth | Discontinue BRUKINSA |
Asymptomatic lymphocytosis in CLL and MCL should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.
Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.
Capsules: Each 80 mg capsule is a size 0, white to off-white opaque capsule marked with "ZANU 80" in black ink.
Tablets: 160 mg, blue, oval, film-coated tablets debossed with "zanu" on one side and functional scoring on the other side.
Drug interactions
Recommended dosage modifications of BRUKINSA for drug interactions are provided in Table 1 [see Drug Interactions (7.1)].
| Coadministered Drug | Recommended BRUKINSA Dosage (Starting Dose: 160 mg twice daily or 320 mg once daily) |
|---|---|
| Clarithromycin 250 mg twice dailySince clarithromycin 250 mg twice daily acts as a moderate CYP3A inhibitor, it is recommended that patients be administered clarithromycin 250 mg twice daily with 80 mg BRUKINSA twice daily [see Clinical Pharmacology (12.3)]. | 80 mg twice dailyModify or interrupt zanubrutinib dose as recommended for adverse reactions [see Dosage and Administration (2.4)]. |
| Clarithromycin 500 mg twice daily | 80 mg once daily |
| Posaconazole suspension 100 mg once daily | 80 mg twice daily |
| Posaconazole suspension dosage higher than 100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole intravenous 300 mg 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 these inducers cannot be avoided, increase BRUKINSA dose to 320 mg twice daily. |
After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA [see Dosage and Administration (2.1, 2.2) and Drug Interactions (7.1)].
• CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. (2.3, 7.1) • CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers. (2.3, 7.1) 7.1 Effect of Other Drugs on BRUKINSA Table 17: Drug Interactions that Affect Zanubrutinib Moderate and Strong CYP3A Inhibitors Clinical Impact • Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may increase the risk of BRUKINSA toxicities. Prevention or management • Reduce BRUKINSA dosage when coadministered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3)]. Moderate and Strong CYP3A Inducers Clinical Impact • Coadministration with a moderate or strong CYP3A inducer decreases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy. Prevention or management • Avoid coadministration of BRUKINSA with strong CYP3A inducers [see Dosage and Administration (2.3)]. • Avoid coadministration of BRUKINSA with moderate CYP3A inducers [see Dosage and Administration (2.3)]. If these inducers cannot be avoided, increase BRUKINSA dosage to 320 mg twice daily [see Dosage and Administration (2.3)].