DRUG INTERACTIONS

• CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. 

• CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers.

ADR-  The most common adverse reactions (= 20%) included neutrophil count decreased, platelet count decreased, upper respiratory tract infection, white blood cell count decreased, hemoglobin decreased, rash, bruising, diarrhea and cough. 

CI-   None. 

WARNINGS AND PRECAUTIONS

Hemorrhage:                                                                                                               Monitor for bleeding and manage appropriately. 

Infections:                                                                                                                Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed.

 ADVERSE REACTIONS

 The most common adverse reactions (= 20%) included neutrophil count decreased, platelet count decreased, upper respiratory tract infection, white blood cell count decreased, hemoglobin decreased, rash, bruising, diarrhea and cough. 

CONTRAINDICATIONS

 None. 

WARNINGS AND PRECAUTIONS

Hemorrhage:                                                                                                               Monitor for bleeding and manage appropriately. 

Infections:                                                                                                                Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat as needed. 

Cytopenias:                                                                                                              Monitor complete blood counts during treatment. 

Second Primary Malignancies:                                                                                 Other malignancies have occurred in patients including skin cancers. Advise patients to use sun protection. 

Cardiac Arrhythmias: Monitor for atrial fibrillation and atrial flutter and manage appropriately. 

Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to avoid pregnancy. 

 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Patient Information).

Hemorrhage                                                                                                               Inform patients to report signs or symptoms of severe bleeding. Inform patients that BRUKINSA may need to be interrupted for major surgeries or procedures

Infections                                                                                                                     Inform patients to report signs or symptoms suggestive of infection

Cytopenias                                                                                                                   Inform patients that they will need periodic blood tests to check blood counts during treatment with BRUKINSA 

Second Primary Malignancies                                                                                 Inform patients that other malignancies have been reported in patients who have been treated with BRUKINSA, including skin cancer. Advise patients to use sun protection 

Cardiac Arrhythmias                                                                                             Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort 

Embryo-Fetal Toxicity                                                                                                Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for at least 1 week after the last dose of BRUKINSA.

Advise males with female sexual partners of reproductive potential to use effective contraception during BRUKINSA treatment and for at least 1 week after the last dose of BRUKINSA  

Lactation                                                                                                                    Advise females not to breastfeed during treatment with BRUKINSA and for at least 2 weeks after the last dose 

Administration Instructions                                                                              BRUKINSA may be taken with or without food.                                                            Advise patients that BRUKINSA capsules should be swallowed whole with a glass of water, without being opened, broken, or chewed.

Missed Dose                                                                                                                Advise patients that if they miss a dose of BRUKINSA, they may still take it as soon as possible on the same day with a return to the normal schedule the following day 

Drug Interactions                                                                                                         Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products 

Distributed and Marketed by: BeiGene USA, Inc. San Mateo, CA 94403 BRUKINSA™ is a trademark owned by BeiGene, Ltd. © BeiGene, Ltd. 2019

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                      Zanubrutinib is a small-molecule inhibitor of BTK. Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.

2. Pharmacodynamics                                                                                                 BTK Occupancy in PBMCs and Lymph Nodes                                                              The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a total daily dose of 320 mg in patients with B-cell malignancies.

The median steady-state BTK occupancy in lymph nodes was 94% to 100% following the approved recommended dosage.

Cardiac Electrophysiology At the approved recommended doses (160 mg twice daily or 320 mg once daily), there were no clinically relevant effects on the QTc interval. The effect of BRUKINSA on the QTc interval above the therapeutic exposure has not been evaluated.

3. Pharmacokinetics                                                                                        Zanubrutinib maximum plasma concentration (Cmax) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dosage range from 40 mg to 320 mg (0.13 to 1 time the recommended total daily dose).

Limited systemic accumulation of zanubrutinib was observed following repeated administration.

Absorption                                                                                                                     The median tmax of zanubrutinib is 2 hours. 

Effect of Food                                                                                                                 No clinically significant differences in zanubrutinib AUC or Cmax were observed following administration of a high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects.

Distribution                                                                                                                    The geometric mean (%CV) apparent steady-state volume of distribution of zanubrutinib is 881 (95%) L. The plasma protein binding of zanubrutinib is approximately 94% and the blood-toplasma ratio is 0.7 to 0.8.

Elimination                                                                                                                    The mean half-life (t½) of zanubrutinib is approximately 2 to 4 hours following a single oral zanubrutinib dose of 160 mg or 320 mg. The geometric mean (%CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37%) L/h.

Metabolism                                                                                                              Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.

Excretion                                                                                                                   Following a single radiolabeled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in feces (38% unchanged) and 8% in urine (less than 1% unchanged).

Specific Populations                                                                                                      No clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, Caucasian, and Other), body weight (36 to 140 kg), or mild or moderate renal impairment (creatinine clearance [CLcr] = 30 mL/min as estimated by Cockcroft-Gault).

The effect of severe renal impairment (CLcr < 30 mL/min) and dialysis on zanubrutinib pharmacokinetics is unknown.

Hepatic Impairment The total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function.

 USE IN SPECIFIC POPULATIONS

1. 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.

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.

2. 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 at least two weeks following the last dose.

3. Females and Males of Reproductive Potential Pregnancy Testing                          Pregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.

Contraception                                                                                                        Females                                                                                                                 BRUKINSA can cause embryo-fetal harm when administered to pregnant women 

Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA and for at least 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 at least 1 week following the last dose of BRUKINSA.

4 Pediatric Use                                                                                                            Safety and effectiveness in pediatric patients have not been established. 

5. Geriatric Use                                                                                                                  Of the 641 patients in clinical studies with BRUKINSA, 49% were = 65 years of age, while 16% were = 75 years of age. No overall differences in safety or effectiveness were observed between younger and older patients.

6. Renal Impairment                                                                                                          No dosage modification is recommended in patients with mild                                          Monitor for BRUKINSA adverse reactions in patients with severe renal impairment (CLcr < 30 mL/min) or on dialysis [see Clinical Pharmacology (12.3)].

7. Hepatic Impairment                                                                                               Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment

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.