Brukinsa Zanubrutinib Capsules For CLL/SLL 80mg*64

[Generic name]: Zebutinib Capsules
[Trade name]: Brukinsa
[Ingredients]: The active ingredient of this product is Zebutinib. Chemical name: (S)-7-[4-(1-acryloylpiperidinyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Molecular formula: C27H29N5O3 Molecular weight: 471.55
[Properties]: This product is a white to off-white hard capsule, and the contents are white to off-white powder.
[Indications]: BRUKINSA is used to treat adults with:

• Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• Waldenström’s macroglobulinemia (WM).
• Mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer.
• Marginal zone lymphoma (MZL) when the disease has come back or did not respond to treatment and who have received at least one certain type of treatment.
• Follicular lymphoma (FL), in combination with the medicine obinutuzumab, when the disease has come back or did not respond to treatment and who have received at least two prior treatments.

[Dosage and Administration]: This product must be used under the guidance of a physician with experience in the treatment of hematologic tumors. It should be taken orally at a roughly fixed time each day. The whole capsule should be taken with water, either before or after meals. Do not open, break or chew the capsule. If this product is not taken at the scheduled time, the patient should take it orally at a roughly fixed time each day. The whole capsule should be taken with water, either before or after meals. Do not open, break or chew the capsule. If this product is not taken at the scheduled time, the patient should take it as soon as possible based on an interval of at least 8 hours between adjacent doses, and resume the normal medication schedule afterwards. Do not take additional doses of this product to make up for missed doses. The recommended dose is 160 mg (2 80 mg capsules) each time, orally, twice a day until disease progression or intolerable toxicity occurs. Dose adjustment when co-administered with CYP3A inhibitors or inducers Dose adjustment when co-administered with CYP3A inhibitors or inducers is shown in Table 1 (see [Drug Interactions] and [Pharmacokinetics]). After discontinuing the CYP3A inhibitor, resume the dose of this product before dose adjustment (see [Dosage and Administration] Recommended dose and dose adjustment for patients with hepatic impairment and [Drug Interactions]). Dose adjustment when adverse reactions occur No dose adjustment is recommended for patients with mild to moderate hepatic impairment. The recommended dose for patients with severe hepatic impairment is 80 mg (1 80 mg capsule) taken orally twice a day (see [Precautions] Special populations and [Pharmacokinetics]). Renal impairment No dose adjustment is recommended for patients with renal impairment. 
[Adverse reactions]: For details of the following adverse reactions, please refer to the instructions [Precautions]. Bleeding Hematocytopenia Hepatitis B virus reactivation. Second primary malignancy Arrhythmia Tumor lysis syndrome Clinical trial experience Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared with the incidence in the clinical trials of another drug, and may not reflect the incidence observed in practice. Summary of safety characteristics The safety information of zanubrutinib comes from six single-drug clinical trials: B31111 B31205, B311207, B-111 1020 BOB 311010) B3B111-100) involving a total of 671 patients. The median administration time of this product is 12.1 months (range: 0.1-46.9 months). Among them, 554 patients received this product twice daily, 160 mg each time, with a median dosing time of 10.5 months (range: 0.1-42.7 months). The most common adverse reactions (210%) in the above six trials were neutropenia, thrombocytopenia, rash, bruising and leukocytopenia. The incidence of grade 3 or above adverse reactions was 34.0%. Common adverse reactions and grade 3 or above adverse reactions are shown in Table 3. Table 3 shows the incidence of common adverse reactions (25%) and grade 3 or above adverse reactions in patients treated with zanubrutinib. The incidence of serious adverse reactions was 14.0%, and the most common (21%) was infectious pneumonia (5.1%). 3.4% of patients experienced adverse reactions that led to dose reduction. 17.6% of patients discontinued dosing due to adverse reactions, the most common (21%) were neutropenia (3.9%), pneumonia (2.8%), thrombocytopenia (1.5%) and bleeding (1.0%). 4.5% of patients permanently discontinued treatment with this product due to adverse reactions, the most common 88U (21%) was pneumonia (1.2%). Mantle cell lymphoma (MCL) The following safety data are based on a single-arm, phase 2 pivotal clinical trial (BGB, 311-206). This trial was conducted in 86 patients with MCL who had received ≥1 line of treatment before, with a median age of 61 years (range: 2:34-75 years). The baseline ECOG score was 0 or 1 (69.8% and 25.6%, respectively). Patients received 160 mg of this product twice a day for a median treatment period of 178 months (range: 0.2-23.5 months). The most common adverse reactions (≥10%) were neutropenia (47.7%), rash (32.6%), leukopenia (31.4%), thrombocytopenia (30.2%), and anemia (11.6%). The incidence of grade 3 or higher adverse reactions was 30.2%, of which those with an incidence of ≥2% included neutropenia (18.6%), infectious pneumonia (7.0%), leukopenia (7.0%), thrombocytopenia (4.7%), anemia (3.5%), and interstitial lung disease (2.3%). The incidence of serious adverse reactions was 15.1%, and the most common (≥20) were pneumonia (8.1%), hemorrhage (2.3%), and thrombocytopenia (2.3%)-adverse reactions led to dosing interruption in 14.0% of patients, the most common of which was pneumonia (3.5%); 2.3% of patients had adverse reactions that led to dose reduction, of which 1 was hepatitis B infection (1.2%). 8.1% of patients discontinued treatment due to adverse reactions, the most common of which was pneumonia (2.3%). Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) This trial is a single-arm, phase 2 pivotal clinical trial (BGB-3111-205) conducted in 91 patients with CLL/SLL who had received ≥1 line of treatment. The median age of the patients was 61 years (range: 35-87 years), and the baseline ECOG score was mainly 0 or 1 (46.2% and 50.5%, respectively). Patients received 160 mg of this product twice daily for a median treatment duration of 13.7 months (range: 90.2-21.2 months). The most common adverse reactions (210%) were neutropenia (68.1%), thrombocytopenia (40.7%), hematuria (35.2%), purpura (34.1%), anemia (23.1%), leukocytopenia (18.7%), pneumonia (18.7%), upper respiratory tract infection (15.4%), hemorrhage (14.3%), and rash (12.1%). The incidence of grade 3 or above adverse reactions was 69.2%, and the most common (22%) were neutropenia (44.0%), thrombocytopenia (15.4%), infectious pneumonia (13.2%), anemia (6.6%), decreased neutrophil percentage (6.6%), hypokalemia (4.4%), leukopenia (4.0%), diarrhea (2.2%), infectious enteritis (2.2%), hepatitis B virus reactivation (2.2%), upper respiratory tract infection (2.2%) and hyponatremia (2.2%). The incidence of serious adverse reactions was 19.8%, and the most common was infectious pneumonia (11.0%). Adverse reactions led to discontinuation of dosing in 24.2% of patients, with the most common (22%) being infectious brittle inflammation (8.8%), anorectal infection (2.2%), hepatitis B virus reactivation (2.2%), and neutropenia (2.2%); 7.7% of patients had adverse reactions leading to dose reduction, with the most common (≥2%) being infectious pneumonia (3.3%) and hepatitis B virus reactivation (2.2%). 6.6% of patients discontinued treatment due to adverse reactions, the most common of which was infectious pneumonia (3.3%).
[Contraindications]: This product is contraindicated in patients who have hypersensitivity to zanubrutinib or excipients (such as anaphylaxis and anaphylaxis-like reactions).

[Precautions] Bleeding Severe bleeding and fatal bleeding events have occurred in patients treated with this product. 2.2% of patients experienced grade 3 or higher bleeding events, of which 0.3% of patients experienced hematuria and gastrointestinal bleeding, respectively. 46.5% of patients experienced bleeding events of varying degrees, with petechiae/purpura/bruises and hematuria being common (>10%). 0.1%, 3.4% and 1.0% of patients reduced the dose of this product, suspended and terminated treatment due to bleeding, respectively. The mechanism of bleeding events is unclear. This product may increase the risk of bleeding in patients receiving antiplatelet or anticoagulant therapy, and patients should be monitored for signs of bleeding. Patients who need surgery should undergo a risk-benefit assessment based on the type of surgery and the risk of bleeding, and consider suspending this product for 3-7 days before and after surgery. If treatment-related bleeding of grade 3 or above or any grade of intracranial hemorrhage occurs, treatment with this product should be permanently discontinued. Cytopenia In patients with hematological malignancies treated with this product, cytopenia is very common, manifested as neutropenia, thrombocytopenia and anemia, and grade 3 or 4 cytopenia is often reported (see [Adverse Reactions]). Common (≥1%) patients interrupted treatment due to neutropenia (5.8%), thrombocytopenia (1.9%) and anemia (1.0%); occasionally (<1%) patients reduced the dose of this product or terminated treatment due to cytopenia. It is recommended to closely monitor the complete blood cell count during treatment. If cytopenia occurs, symptomatic treatment should be given according to clinical needs; if necessary, the drug should be suspended and resumed after the relevant hematological adverse reactions are alleviated to the conditions for medication (see [Dosage and Administration] for details). Infections Fatal serious infections (including bacteria, viruses or fungi) and opportunistic infections have been reported in patients with hematological malignancies treated with this product. 21.5% of patients experienced infection events of grade 3 or above, the most common of which was infectious pneumonia. Patients at high risk for infection should consider prophylactic treatment for herpes simplex virus, Pneumocystis jiroveci pneumonia, and other infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat accordingly. Hepatitis B virus reactivation Hepatitis B virus reactivation (1.0%) has been reported in clinical trials of this product. In these clinical trials, patients with active hepatitis B were excluded. The effect of this product on hepatitis B virus reactivation is unknown. The hepatitis B virus status should be clarified before using this product. If the patient is currently or has a history of hepatitis B virus infection, it is recommended to consult a hepatitis specialist before starting treatment with this product, and monitor and manage according to local diagnosis and treatment routines to prevent recurrence of hepatitis B. Patients who are positive for hepatitis B core antibodies in clinical trials must receive prophylactic anti-hepatitis B virus treatment. Second primary malignancies There are reports of second primary malignancies with similar products. 7.9% of patients with hematologic malignancies treated with this product as a monotherapy developed a second primary malignancy, the most common of which were skin cancers (basal cell carcinoma [3.6%] and squamous cell carcinoma of the skin [1.9%]). Patients are advised to take sun protection measures. Atrial fibrillation, atrial flutter, and ventricular tachycardia have been reported in clinical trials and post-marketing observations of similar products. Among patients treated with this product, 1.8% of patients experienced atrial fibrillation or atrial flutter events, and 0.4% of patients experienced ventricular premature beats and ventricular arrhythmias. 0.6% of patients experienced grade 3 or higher arrhythmic events. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk for arrhythmias. During treatment with this product, patients should be monitored regularly for the development of arrhythmias, and patients who experience symptoms of arrhythmias (such as palpitations, dizziness, syncope, chest discomfort, or new dyspnea) should be clinically evaluated and undergo electrocardiogram (ECG) examinations as indicated. When atrial fibrillation occurs, treatment should be adjusted promptly (see [Dosage and Administration]). For patients with symptomatic and/or incompletely controlled atrial fibrillation, after atrial fibrillation is adequately controlled, this product can be restarted at the starting dose or at half the dose (e.g., starting with 160 mg twice a day, then reduce to 80 mg twice a day; if starting with 80 mg twice a day, then reduce to 80 mg once a day) based on the doctor's assessment. Tumor lysis syndrome Cases of tumor lysis syndrome have been reported when this product is used for treatment, especially in patients with CLL receiving treatment. Baseline risks (such as high tumor burden) should be assessed and appropriate preventive measures should be taken. Closely monitor patients and give appropriate treatment. Special populations Hepatic impairment The safety of this product in patients with severe hepatic impairment has not been established. It is recommended to adjust the dose of this product in patients with severe hepatic impairment (see [Dosage and Administration]). It is not recommended to change the dose in patients with mild to moderate hepatic impairment. Patients with hepatic impairment should be monitored for adverse reactions when receiving this product (see [Pharmacokinetics]). Renal impairment This product is eliminated very little through the kidney. Patients with mild and moderate renal impairment were enrolled in clinical trials, and the pharmacokinetic characteristics of this product have not been evaluated in patients with severe renal impairment or patients with renal impairment requiring dialysis. No dose adjustment is recommended for patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min, estimated according to the Cockcroft-Gault formula). Patients with severe renal impairment (creatinine clearance < 30 mL/min) or dialysis should be monitored for related adverse reactions when using this product. Pregnancy testing for women of childbearing age and men Before starting treatment with this product, women of childbearing potential should be checked for pregnancy status. Contraception This product may produce embryo-fetal toxicity (see [Pharmacology and Toxicology]). Women of childbearing potential are advised to take highly effective contraceptive measures during treatment with this product and within 1 week after treatment. If this product is taken during pregnancy or becomes pregnant while taking this product, the patient should be clearly informed that this product may cause harm to the fetus. Men are advised to take highly effective contraceptive measures during treatment with this product and within 1 week after treatment. Effects on the ability to drive or use machines Studies have not been conducted to evaluate the effects of this drug on the ability to drive or use machines. Others Keep out of the reach of children.

[Precautions for children]: The safety and efficacy of this product in pediatric patients have not been established.
[Precautions for pregnancy and lactation]: It is recommended that women should avoid pregnancy and breastfeeding while taking this product. If this product is used during pregnancy or the patient becomes pregnant while taking this product, the patient should be informed of the potential harm of this product to the fetus (see [Precautions]). There is currently no data on whether this product and its metabolites are secreted through human milk, whether they will affect breastfed infants or milk production. Breastfeeding may cause serious adverse reactions to infants due to this product, so it is recommended that lactating women do not breastfeed during treatment with this product and for at least two weeks after the last dose.
[Precautions for the elderly]: In the key clinical trials of this product for MCL (BGB-3111-206) and CLL/SLL (BGB-3111-205), patients aged ≥65 years accounted for 25.6% and 34.1%, respectively. No dose adjustment is required for elderly patients due to age factors. No overall differences in safety or efficacy were observed between young and elderly patients.
[Drug Interactions]: Effects of CYP3A Inhibitors on Zanubrutinib Clinical Effects of Moderate or Strong CYP3A Inhibitors Zanubrutinib co-administered with moderate or strong CYP3A inhibitors will increase the exposure of Zanubrutinib (see [Pharmacokinetics]). Increased exposure to Zanubrutinib may result in increased drug-related toxicity. Prevention or Management When Zanubrutinib is co-administered with moderate or strong CYP3A inhibitors, the dose of Zanubrutinib should be reduced (see [Dosage and Administration]). Effects of CYP3A Inducers on Zanubrutinib Clinical Effects of Moderate or Strong CYP3A Inducers Zanubrutinib co-administered with moderate or strong CYP3A inducers will reduce the exposure of Zanubrutinib (see [Pharmacokinetics]). Reduced exposure may reduce the efficacy of Zanubrutinib. Prevention or Management Avoid co-administration of Zanubrutinib with moderate or strong CYP3A inducers. Consider administering alternative medications with weaker CYP3A induction effects (see [Dosage and Administration]).

[Pharmacological action]: Pharmacological action Zebutinib is a selective inhibitor of Bruton's tyrosine kinase (BTK). It inhibits BTK activity by covalently binding to the cysteine ​​at site 481 of the BTK protein, thereby inhibiting its tyrosine phosphorylation at site 223. BTK is a key regulator of the B cell receptor (BCR) signaling pathway and plays an important role in B cell proliferation, apoptosis, differentiation and development. In vivo experiments showed that Zebutinib inhibited the growth of Rec-1 mantle cell lymphoma cells and TMD-8 diffuse large B lymphoma cells in a dose-dependent manner. Toxicological studies General toxicity: In the 1-month repeated-dose toxicity test in rats, the main toxic target organs were pancreas, skin, spleen, prostate, uterus and large intestine, and the maximum tolerated dose (MTD) was 500 mg/kg/d (based on AUC, it is approximately 46.4 times [female] and 25.8 times [male] of the recommended human dose of 160 mg/time [BID]); in the 13-week repeated-dose toxicity test in rats, the main toxic target organs were pancreas and lungs, and the MTD was 300 mg/kg/d (based on AUC, it is approximately 35.3 times [female] and 12.5 times [male] of the recommended human dose of 160 mg/time [BID]); in the 26-week repeated-dose toxicity test in rats, the main toxic target organs were pancreas, lungs, and skeletal muscle, and the MTD was 300 mg/kg/d (based on AUC, it is approximately 31.9 times [female] and 19 times [male] of the recommended human dose of 160 mg/time [BID]). In the 1-month repeated-dose toxicity test in dogs, splenic lymphocytopenia was observed, and the MTD was 100 mg/kg (based on AUC, about 13.7 times the recommended human dose of 160 mg/time [BID]); in the 13-week repeated-dose toxicity test in dogs, lymphocytopenia in the spleen, mesenteric lymph nodes, and mandibular lymph nodes was observed, and the MTD was 100 mg/kg/d (based on AUC, about 12 times the recommended human dose of 160 mg/time [BID]); in the 39-week repeated-dose toxicity test in dogs, abnormal stool, conjunctival congestion, and lymphocytopenia or erythrophagocytosis in gastrointestinal-related lymphoid tissues were observed, and the MTD was 100 mg/kg/d (based on AUC, about 14.3 times the recommended human dose of 160 mg/time [BID]). Genotoxicity: The results of the Ames test, human lymphocyte chromosome aberration test, and in vivo micronucleus test in rats were all negative. Reproductive toxicity: When SD rats were orally administered zanubrutinib at 30, 100, and 300 mg/kg/d, no significant effects were observed on the fertility and early embryonic development of the rats. The no-adverse-effect dose (NOAEL) was 300 mg/kg/d (based on body surface area, approximately 9 times the recommended human dose of 160 mg/time [BID]). In the embryo-fetal developmental toxicity study, pregnant rats were orally administered zanubrutinib at 30, 75, and 150 mg/kg/d during the period of organogenesis (approximately 4, 12.6, and 16.4 times the recommended human dose of 160 mg/time [BID], respectively, based on AUC). There was 1 case of three-chambered heart (0.3%), 1 case of two-chambered heart (0.3%), and 5 cases of three-chambered heart (1.5%), respectively; pregnant rabbits were orally administered zanubrutinib at 30, 75, and 150 mg/kg/d during the period of organogenesis, and no teratogenic effects were observed. The NOAEL for maternal toxicity and embryo-fetal developmental toxicity was 150 mg/kg/d (approximately 25.3 times the recommended human dose of 160 mg/time [BID], based on AUC). In the perinatal toxicity study, pregnant rats were orally administered zanubrutinib at 30, 75, and 150 mg/kg/d (approximately 0.9, 2.4, and 4.8 times the recommended human dose of 160 mg/time [BID], based on body surface area), and the F1 generation showed drug-related eye abnormalities: the pupil did not fully dilate after dilation, and was often accompanied by medium-sized or larger nuclear cataracts, intraocular structures that could not be examined or the fundus was unclear, and small multi-punctate corneal opacities, indicating an inflammatory response in the eye and affecting multiple tissues in the eye; a few F1 animals had a low incidence (monocular disease) of iris adhesion, pupillary residual membrane, anterior chamber hemorrhage, corneal neovascularization, enlarged or smaller eyes, lens dislocation, retinal hemorrhage, iris congestion, and corneal pigment deposition, which could not be ruled out as unrelated to the drug; the F0 generation in the group ≥75 mg/kg/d showed transient, mild drooling, lip swelling, and red/brown foreign bodies around the nose that were related to the drug. Carcinogenicity: No carcinogenicity studies have been conducted on zanubrutinib.

[Long-term medication management]:
Regular monitoring:
Monthly blood routine examination, liver and kidney function, and assessment of bleeding and infection risks.
Imaging examinations (such as CT) are performed every 6-12 months to monitor tumor progression.[Discontinuation conditions]:
Drug resistance: If BTK target resistance mutations (such as C481S) occur, the drug should be discontinued and other treatment options should be used.
Serious side effects: If bleeding above grade 3, infection, arrhythmia, etc. occur, the drug should be discontinued immediately.
[Storage]: Sealed, stored below 30°C.
[Specifications]: 80mg*64 tablets*1 bottle
[Packaging specifications]: Oral solid pharmaceutical high-density polyethylene bottle and high-density polyethylene/polypropylene child-safe combination bottle cap system. 64 capsules/bottle/box.
[Validity period]: 24 months.
[Implementation standard]: Implementation standard] YBH01572020
[Approval number]: National medicine standard H20200005
[Company name]: BeiGene Biotechnology Co., Ltd.