NDC 72579-011 Brukinsa

Zanubrutinib

NDC Product Code 72579-011

NDC CODE: 72579-011

Proprietary Name: Brukinsa What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Zanubrutinib What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE)
Shape: CAPSULE (C48336)
Size(s):
22 MM
Imprint(s):
ZANU;80
Score: 1

NDC Code Structure

NDC 72579-011-01

Package Description: 60 CAPSULE, GELATIN COATED in 1 BOTTLE, PLASTIC

NDC 72579-011-02

Package Description: 120 CAPSULE, GELATIN COATED in 1 BOTTLE, PLASTIC

NDC Product Information

Brukinsa with NDC 72579-011 is a a human prescription drug product labeled by Beigene Usa, Inc.. The generic name of Brukinsa is zanubrutinib. The product's dosage form is capsule, gelatin coated and is administered via oral form.

Labeler Name: Beigene Usa, Inc.

Dosage Form: Capsule, Gelatin Coated - A solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin; through a banding process, the capsule is coated with additional layers of gelatin so as to form a complete seal.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Brukinsa Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ZANUBRUTINIB 80 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Beigene Usa, Inc.
Labeler Code: 72579
FDA Application Number: NDA213217 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 11-18-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Brukinsa Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

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.

2.1 Recommended Dosage

The recommended dose of BRUKINSA 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.

2.2 Dosage Modification For Use In Hepatic Impairment

The recommended dose 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)].

2.3 Dosage Modifications For Drug Interactions

Recommended dose modifications of BRUKINSA for drug interactions are provided in Table 1 [see Drug Interactions (7.1)].Table 1: Dose Modifications for Use With CYP3A Inhibitors or InducersCo-administered DrugRecommended BRUKINSA DoseStrong CYP3A inhibitor 80 mg once dailyInterrupt dose as recommended for adverse reactions [see Dosage and Administration (2.4)].Moderate CYP3A inhibitor 80 mg twice dailyModify dose as recommended for adverse reactions [see Dosage and Administration (2.4)].Moderate or strong CYP3A inducerAvoid concomitant use.After discontinuation of a CYP3A inhibitor, resume previous dose of BRUKINSA [see Dosage and Administration (2.1, 2.2) and Drug Interactions (7.1)].

2.4 Dosage Modifications For Adverse Reactions

Recommended dose modifications of BRUKINSA for Grade 3 or higher adverse reactions are provided in Table 2:Table 2: Recommended Dose Modification for Adverse ReactionEventAdverse Reaction OccurrenceDose Modification(Starting Dose: 160 mg twice daily or 320 mg once daily)Grade 3 or higher non-hematological toxicities Grade 3 febrile neutropenia Grade 3 thrombocytopenia with significant bleeding Grade 4 neutropenia (lasting more than 10 consecutive days) Grade 4 thrombocytopenia (lasting more than 10 consecutive days)FirstInterrupt BRUKINSAOnce toxicity has resolved to recovery to Grade 1 or lower or baseline: Resume at 160 mg twice daily or 320 mg once dailySecondInterrupt BRUKINSAOnce toxicity has resolved to recovery to Grade 1 or lower or baseline: Resume at 80 mg twice daily or 160 mg once dailyThirdInterrupt BRUKINSAOnce toxicity has resolved to recovery to Grade 1 or lower or baseline: Resume at 80 mg once dailyFourthDiscontinue BRUKINSAAsymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.

3 Dosage Forms And Strengths

Capsules: Each 80 mg capsule is a size 0, white to off-white opaque capsule marked with "ZANU 80" in black ink.

4 Contraindications

None.

5.1 Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration 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 pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

5.2 Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci 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 (27%), thrombocytopenia (10%), and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

5.4 Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

5.5 Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

5.6 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 at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 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)].

6 Adverse Reactions

  • 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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA as a single agent at 160 mg twice daily in 524 patients in clinical trials BGB-3111-AU-003, BGB-3111-206, BGB-3111-205, BGB-3111-210, and BGB-3111-1002 and to BRUKINSA at 320 mg once daily in 105 patients in trials BGB-3111-AU-003 and BGB-3111-1002. Among 629 patients receiving BRUKINSA, 79% were exposed for 6 months or longer and 61% were exposed for greater than one year.In this pooled safety population, the most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%).

Other

Mantle Cell Lymphoma (MCL)The safety of BRUKINSA was evaluated in 118 patients with MCL who received at least one prior therapy in two single-arm clinical trials, BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120] [see Clinical Studies (14.1)]. The median age of patients who received BRUKINSA in studies BGB-3111-206 and BGB-3111-AU-003 was 62 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, and 94% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior lines of therapy (range: 1 to 4). The BGB-3111-206 trial required a platelet count ≥ 75 × 109/L and an absolute neutrophil count ≥ 1 × 109/L independent of growth factor support, hepatic enzymes ≤ 2.5 × upper limit of normal, total bilirubin ≤ 1.5 × ULN. The BGB-3111-AU-003 trial required a platelet count ≥ 50 × 109/L and an absolute neutrophil count ≥ 1 × 109/L independent of growth factor support, hepatic enzymes ≤ 3 × upper limit of normal, total bilirubin ≤ 1.5 × ULN. Both trials required a CLcr ≥ 30 mL/min. Both trials excluded patients with prior allogeneic hematopoietic stem cell transplant, exposure to a BTK inhibitor, known infection with HIV, and serologic evidence of active hepatitis B or hepatitis C infection and patients requiring strong CYP3A inhibitors or strong CYP3A inducers. Patients received BRUKINSA 160 mg twice daily or 320 mg once daily. Among patients receiving BRUKINSA, 79% were exposed for 6 months or longer and 68% were exposed for greater than one year.Fatal events within 30 days of the last dose of BRUKINSA occurred in 8 (7%) of 118 patients with MCL. Fatal cases included pneumonia in 2 patients and cerebral hemorrhage in one patient.Serious adverse reactions were reported in 36 patients (31%). The most frequent serious adverse reactions that occurred were pneumonia (11%), and hemorrhage (5%).Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).Table 3 summarizes the adverse reactions in BGB-3111-206 and BGB-3111-AU-003.Table 3: Adverse Reactions (≥ 10%) in Patients Receiving BRUKINSA in BGB-3111-206 and BGB-3111-AU-003 TrialsBody SystemAdverse ReactionPercent of Patients (N=118)All Grades %Grade 3 or Higher %Blood and lymphatic system disordersNeutropenia and Neutrophil count decreased3815Thrombocytopenia and Platelet count decreased275Leukopenia and White blood count decreased255Anemia and Hemoglobin decreased148Infections and infestationsUpper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral390Pneumonia Pneumonia includes pneumonia, pneumonia fungal, pneumonia cryptococcal, pneumonia streptococcal, atypical pneumonia, lung infection, lower respiratory tract infection, lower respiratory tract infection bacterial, lower respiratory tract infection viral1510Includes fatal adverse reactionUrinary tract infection110.8Skin and subcutaneous tissue disordersRash Rash includes all related terms containing rash360Bruising Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis140Gastrointestinal disordersDiarrhea230.8Constipation130Vascular disordersHypertension123.4Hemorrhage Hemorrhage includes all related terms containing hemorrhage, hematoma113.4Musculoskeletal and connective tissue disordersMusculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis143.4Metabolism and nutrition disordersHypokalemia141.7Respiratory, thoracic and mediastinal disordersCough120Other clinically significant adverse reactions that occurred in < 10% of patients with mantle cell lymphoma include major hemorrhage (defined as ≥ Grade 3 hemorrhage or CNS hemorrhage of any grade) (5%), hyperuricemia (6%) and headache (4.2%).Table 4: Selected Laboratory AbnormalitiesBased on laboratory measurements. (> 20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003Laboratory ParameterPercent of Patients (N=118)All Grades (%)Grade 3 or 4 (%)  Neutrophils decreased4520  Platelets decreased407  Hemoglobin decreased276  Lymphocytosis Asymptomatic lymphocytosis is a known effect of BTK inhibition.4116Chemistry abnormalities  Blood uric acid increased292.6  ALT increased280.9  Bilirubin increased240.9

Risk SummaryBased 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 DataEmbryo-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 post-implantation 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 post-natal 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.

Risk SummaryThere 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.

Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy.

Contraception

FemalesBRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. 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.

MalesAdvise men to avoid fathering a child while receiving BRUKINSA and for at least 1 week following the last dose of BRUKINSA.

BTK Occupancy in PBMCs and Lymph NodesThe 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 ElectrophysiologyAt 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.

AbsorptionThe median tmax of zanubrutinib is 2 hours.

Effect of FoodNo 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.

DistributionThe 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-to-plasma ratio is 0.7 to 0.8.

EliminationThe 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.

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

ExcretionFollowing 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 PopulationsNo 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 ImpairmentThe 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. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepatic impairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

CYP3A Inhibitors: Co-administration of multiple doses of CYP3A inhibitors increases zanubrutinib Cmax and AUC (Table 6).Table 6: Observed or Predicted Increase in Zanubrutinib Exposure After Co-Administration of CYP3A InhibitorsCo-administered CYP3A InhibitorIncrease in Zanubrutinib CmaxIncrease in Zanubrutinib AUCObservedItraconazole (200 mg once daily)157%278%PredictedClarithromycin (250 mg twice daily)175%183%Diltiazem (60 mg three times daily)151%157%Erythromycin (500 mg four times daily)284%317%Fluconazole (200 mg once daily)179%177%Fluconazole (400 mg once daily)270%284%

CYP3A Inducers: Co-administration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib Cmax by 92% and AUC by 93%.Co-administration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib Cmax by 58% and AUC by 60%.

CYP3A Substrates: Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by 30% and AUC by 47%.

CYP2C19 Substrates: Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmax by 20% and AUC by 36%.

Other CYP Substrates: No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics or predicted with rosiglitazone (CYP2C8 substrate) pharmacokinetics when co-administered with zanubrutinib.

Transporter Systems: Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib.

Gastric Acid Reducing Agents: No clinically significant differences in zanubrutinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).

In Vitro Studies

CYP Enzymes: Zanubrutinib is an inducer of CYP2B6.

Transporter Systems: Zanubrutinib is likely to be a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.

How SuppliedPackage SizeContentNDC Number120-countBottle with a child-resistant cap containing 120 capsules72579-011-0280 mg, white to off-white opaque capsule, marked with "ZANU 80" in black ink

HemorrhageInform patients to report signs or symptoms of severe bleeding. Inform patients that BRUKINSA may need to be interrupted for major surgeries or procedures [see Warnings and Precautions (5.1)].

InfectionsInform patients to report signs or symptoms suggestive of infection [see Warnings and Precautions (5.2)].

CytopeniasInform patients that they will need periodic blood tests to check blood counts during treatment with BRUKINSA [see Warnings and Precautions (5.3)].

Second Primary MalignanciesInform patients that other malignancies have been reported in patients who have been treated with BRUKINSA, including skin cancer. Advise patients to use sun protection [see Warnings and Precautions (5.4)].

Cardiac ArrhythmiasCounsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions (5.5)].

Embryo-Fetal ToxicityAdvise 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 [see Warnings and Precautions (5.6)].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 [see Use in Specific Populations (8.3)].

LactationAdvise females not to breastfeed during treatment with BRUKINSA and for at least 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Administration InstructionsBRUKINSA 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 [see Dosage and Administration (2.1)].

Missed DoseAdvise 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 [see Dosage and Administration (2.1)].

Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products [see Drug Interactions (7)].

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

7.1 Effect Of Other Drugs On Brukinsa

  • Table 5:Drug Interactions that Affect ZanubrutinibModerate and Strong CYP3A InhibitorsClinical ImpactCo-administration 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 managementReduce BRUKINSA dosage when co-administered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3)].Moderate and Strong CYP3A InducersClinical ImpactCo-administration with a moderate or strong CYP3A inducer decreases zanubrutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BRUKINSA efficacy.Prevention or managementAvoid co-administration of BRUKINSA with moderate or strong CYP3A inducers [see Dosage and Administration (2.3)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

8.6 Renal Impairment

No dosage modification is recommended in patients with mild to moderate renal impairment (CLcr ≥ 30 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients with severe renal impairment (CLcr < 30 mL/min) or on dialysis [see Clinical Pharmacology (12.3)].

8.7 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)].

11 Description

BRUKINSA (zanubrutinib) is a Bruton's tyrosine kinase (BTK) inhibitor. The empirical formula of zanubrutinib is C27H29N5O3 and the chemical name is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide. Zanubrutinib is a white to off-white powder, with a pH of 7.8 in saturated solution. The aqueous solubility of zanubrutinib is pH dependent, from very slightly soluble to practically insoluble.The molecular weight of zanubrutinib is 471.55 Daltons.Zanubrutinib has the following structure:Each BRUKINSA capsule for oral administration contains 80 mg zanubrutinib and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell contains edible black ink, gelatin, and titanium dioxide.

12.1 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. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth.

12.3 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.The geometric mean (%CV) zanubrutinib steady-state daily AUC is 2,295 (37%) ng∙h/mL following 160 mg twice daily and 2,180 (41%) ng∙h/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state Cmax is 314 (46%) ng/mL following 160 mg twice daily and 543 (51%) ng/mL following 320 mg once daily.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with zanubrutinib.Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30 to 300 mg/kg/day. Male rats were dosed 4 weeks prior to mating and through mating and female rats were dosed 2 weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted but at the highest dose tested, morphological abnormalities in sperm and increased post-implantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.

14.1 Mantle Cell Lymphoma

The efficacy of BRUKINSA was assessed in BGB-3111-206 [NCT03206970], a Phase 2, open-label, multicenter, single-arm trial of 86 previously treated patients with MCL who had received at least one prior therapy. BRUKINSA was given orally at a dose of 160 mg twice daily until disease progression or unacceptable toxicity.The median age of patients was 60.5 years (range: 34 to 75) and the majority were male (78%). The median time since diagnosis to study entry was 30 months (range: 3 to 102) and the median number of prior therapies was 2 (range: 1 to 4). The most common prior regimens were CHOP-based (91%) followed by rituximab-based (74%). The majority of patients had extranodal involvement (71%) and refractory disease (52%). Blastoid variant of MCL was present in 14% of patients. The MIPI score was low in 58%, intermediate in 29%, and high risk in 13%.The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], a Phase 1/2, open-label, dose-escalation, global, multicenter, single-arm trial of B-cell malignancies including 32 previously treated MCL patients treated with BRUKINSA. BRUKINSA was given orally at doses of 160 mg twice daily or 320 mg daily. The median age of patients with previously treated MCL was 70 years (range: 42 to 86), and 38% of patients were ≥ 75 years old. Most patients were male (69%) and Caucasian (78%). The MIPI score was low in 28%, intermediate in 41%, and high risk in 31%.Tumor response was according to the 2014 Lugano Classification for both studies, and the primary efficacy endpoint was overall response rate as assessed by an Independent Review Committee.Table 7: Efficacy Results in Patients with MCL by Independent Review CommitteeStudy BGB-3111-206 (N=86)Study BGB-3111-AU-003 (N=32)ORR: overall response rate, CR: complete response, PR: partial response, DoR: duration of response, CI: confidence interval, NE: not estimableORR (95% CI)84% (74, 91)84% (67, 95)CR59%22%FDG-PET scans were not required for response assessmentPR24%62%Median DoR in months (95% CI)19.5 (16.6, NE)18.5 (12.6, NE)

Storage And Handling

StorageStore at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

17 Patient Counseling Information

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

Spl Patient Package Insert

  • PATIENT INFORMATION BRUKINSA™ (BROO-kin-sah) (zanubrutinib) capsules  This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 11/2019  What is BRUKINSA?BRUKINSA is a prescription medicine used to treat adults with mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.It is not known if BRUKINSA is safe and effective in children.Before taking BRUKINSA, tell your healthcare provider about all of your medical conditions, including if you:have bleeding problems.have had recent surgery or plan to have surgery. Your healthcare provider may stop BRUKINSA for any planned medical, surgical, or dental procedure.have an infection.have or had heart rhythm problems.have high blood pressure.have liver problems, including a history of hepatitis B virus (HBV) infection.are pregnant or plan to become pregnant. BRUKINSA can harm your unborn baby. If you are able to become pregnant, your healthcare provider may do a pregnancy test before starting treatment with BRUKINSA.Females should not become pregnant during treatment and for at least 1 week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least 1 week after the last dose of BRUKINSA.Males should avoid getting female partners pregnant during treatment and for at least 1 week after the last dose of BRUKINSA. You should use effective birth control (contraception) during treatment and for at least 1 week after the last dose of BRUKINSA.are breastfeeding or plan to breastfeed. It is not known if BRUKINSA passes into your breast milk. Do not breastfeed during treatment with BRUKINSA and for at least 2 weeks after your last dose of BRUKINSA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking BRUKINSA with certain other medications may affect how BRUKINSA works and can cause side effects.How should I take BRUKINSA?Take BRUKINSA exactly as your healthcare provider tells you to take it.Do not change your dose or stop taking BRUKINSA unless your healthcare provider tells you to.Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking BRUKINSA if you develop certain side effects.Take BRUKINSA with or without food.Swallow BRUKINSA capsules whole with a glass of water. Do not open, break, or chew the capsules.If you miss a dose of BRUKINSA, take it as soon as you remember on the same day. Return to your normal schedule the next day.What are the possible side effects of BRUKINSA?BRUKINSA may cause serious side effects, including:Bleeding problems (hemorrhage) that can be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:blood in your stools or black stools (looks like tar)pink or brown urineunexpected bleeding, or bleeding that is severe or you cannot controlvomit blood or vomit that looks like coffee groundscough up blood or blood clotsincreased bruisingdizzinessweaknessconfusionchanges in speechheadache that lasts a long timeInfections that can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, or flu-like symptoms.Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with BRUKINSA, but can also be severe. Your healthcare provider should do blood tests during treatment with BRUKINSA to check your blood counts.Second primary cancers. New cancers have happened in people during treatment with BRUKINSA, including cancers of the skin. Use sun protection when you are outside in sunlight.Heart rhythm problems (atrial fibrillation and atrial flutter). Tell your healthcare provider if you have any of the following signs or symptoms:your heartbeat is fast or irregularfeel lightheaded or dizzypass out (faint)shortness of breathchest discomfortThe most common side effects of BRUKINSA include:decreased white blood cellsdecreased platelet countrashdiarrheaupper respiratory infectiondecreased red blood cells (anemia)bruisingcoughThese are not all the possible side effects of BRUKINSA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should I store BRUKINSA?Store BRUKINSA capsules at room temperature between 68°F to 77°F (20°C to 25°C).BRUKINSA comes in a bottle with a child-resistant cap.Keep BRUKINSA and all medicines out of the reach of children.General information about the safe and effective use of BRUKINSA.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use BRUKINSA for a condition for which it was not prescribed. Do not give BRUKINSA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about BRUKINSA that is written for healthcare professionals.What are the ingredients in BRUKINSA?Active ingredient: zanubrutinibInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.Capsule shell contains edible black ink, gelatin, and titanium dioxide.Distributed and Marketed by: BeiGene USA, Inc. San Mateo, CA 94403 BRUKINSA™ is a trademark owned by BeiGene, Ltd. © BeiGene, Ltd. 2019 For more information, go to www.BRUKINSA.com or call 1-833-969-2463.

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