Brukinsa
(zanubrutinib)Dosage & Administration
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Brukinsa Prescribing Information
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.
Waldenström's Macroglobulinemia
BRUKINSA is indicated for the treatment of adult patients with Waldenström's macroglobulinemia (WM) [see Clinical Studies (14.2)].
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.
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)].
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.
Recommended 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.
BRUKINSA can be taken with or without food. Advise patients to swallow capsules whole with water. Advise patients not to open, break, or chew the capsules. If a dose of BRUKINSA is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day.
Dosage Modification for Use in Hepatic Impairment
The recommended dosage of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Dosage Modifications for 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 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 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)].
Dosage Modifications for Adverse Reactions
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 | |
| Non-hematological toxicities [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)] | ||
| Severe or life-threatening non-hematological toxicities * | 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.
Pregnancy
Risk Summary
Based on findings in animals, BRUKINSA can cause fetal harm when administered to pregnant women. There are no available data on BRUKINSA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of zanubrutinib to pregnant rats during the period of organogenesis was associated with fetal heart malformation at approximately 5-fold human exposures (see Data). Women should be advised to avoid pregnancy while taking BRUKINSA. If BRUKINSA is used during pregnancy, or if the patient becomes pregnant while taking BRUKINSA, the patient should be apprised of the potential hazard to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Embryo-fetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart (2 or 3-chambered hearts) were noted at all dose levels in the absence of maternal toxicity. The dose of 30 mg/kg/day is approximately 5 times the exposure (AUC) in patients receiving the recommended dose of 160 mg twice daily.
Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day resulted in postimplantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the exposure (AUC) in patients at the recommended dose and was associated with maternal toxicity.
In a pre and postnatal developmental toxicity study, zanubrutinib was administered orally to rats at doses of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from the middle and high dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e.g., cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5 times the AUC in patients receiving the recommended dose.
Lactation
Risk Summary
There are no data on the presence of zanubrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from BRUKINSA in a breastfed child, advise lactating women not to breastfeed during treatment with BRUKINSA and for two weeks following the last dose.
Females and Males of Reproductive Potential
BRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.
Contraception
Females
Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA and for 1 week following the last dose of BRUKINSA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.
Males
Advise men to avoid fathering a child while receiving BRUKINSA and for 1 week following the last dose of BRUKINSA.
Pediatric Use
Safety and effectiveness of BRUKINSA in pediatric patients have not been established.
Geriatric Use
Of the 1729 patients with MCL, MZL, WM, CLL/SLL, and FL in clinical studies with BRUKINSA, 59% were ≥65 years of age, and 21% were ≥75 years of age. Patients ≥65 years of age had numerically higher rates of Grade 3 or higher adverse reactions and serious adverse reactions (57% and 38%, respectively) than patients <65 years of age (51% and 29%, respectively). No overall differences in effectiveness were observed between younger and older patients.
Renal Impairment
No dosage modification is recommended in patients with mild, moderate, or severe renal impairment (CLcr ≥15 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients on dialysis [see Clinical Pharmacology (12.3)].
Hepatic Impairment
Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment [see Dosage and Administration (2.2)]. The safety of BRUKINSA has not been evaluated in patients with severe hepatic impairment. No dosage modification is recommended in patients with mild to moderate hepatic impairment. Monitor for BRUKINSA adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
None.
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.
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.
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.
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.
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.
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.
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)].