繁体中文
设为首页
加入收藏
当前位置:药品说明书与价格首页 >> 肿瘤 >> 新药推荐 >> 依鲁替尼胶囊|Imbruvica(Ibrutinib Capsules)

依鲁替尼胶囊|Imbruvica(Ibrutinib Capsules)

2015-02-07 02:17:41  作者:新特药房  来源:互联网  浏览次数:439  文字大小:【】【】【
简介:Ibrutinib第一个药物获批准治疗Waldenström氏巨球蛋白血症批准日期:2015年1月29日:公司:Pharmacyclics公司和Janssen Biotech公司突破治疗指定,优先审评,和孤儿产品指定FDA的药品评价和研究中心 ...

美国FDA扩展批准Imbruvica为治疗罕见形式非何杰金氏病淋巴瘤
——首个药物被批准治疗Waldenström氏巨球蛋白血症
批准日期:2015年1月29日:公司:Pharmacyclics公司和Janssen Biotech公司
2015年1月29日,美国食品和药品监管局(FDA)扩张批准使用(依鲁替尼 ibrutinib)为患者有Waldenström氏巨球蛋白血症(WM),开始在机体免疫系统癌的一种罕见形式。药物为这个使用接受突破治疗指定。
非霍奇金淋巴瘤的一个类型,WM随时间缓慢变坏和致异常血细胞,被称为B淋巴细胞(B-细胞),在骨髓,淋巴结,肝,和脾内生长。在WM中,异常B-细胞还过度产生一种蛋白被称为免疫球蛋白 M或IgM(巨球蛋白)可能导致过量出血,有视力和有神经系统问题。
按照美国国家癌症研究所,在2014年约70,800名美国人被诊断和18,990死于非霍奇金淋巴瘤。Imbruvica通过阻断允许在WM中异常B-细胞生长和分裂的酶起作用。
FDA的药品评价和研究中心血液学和肿瘤学产品室主任Richard Pazdur,医学博士说:“今天批准强调补充适应证对药物发展的重要性,”“继续研究已发现Imbruvica的新使用。”
在2013年11月 FDA初始授权加速批准为接受一种以前治疗套细胞淋巴瘤患者使用。
2014年2月,FDA授权加速批准Imbruvica为有以前治疗慢性淋巴细胞白血病(CLL)患者中使用,和然后在2014年7月,扩展其使用包括携带染色体17缺失CLL患者的治疗。
FDA基于在一项63例以前治疗参加者临床研究批准Imbruvica对WM,所有研究参加者接受一个每天420 mg口服给予药物直至疾病进展或副作用成为不能耐受。结果显示62%参加者治疗后有其癌症皱缩(总反应率)。该研究时间,反应时间范围从2.8个月至约18.8个月。
随药物最常见副作用伴是低血小板计数(血小板减少),与感染斗争白细胞减低(中性粒细胞减少),腹泻,低红细胞计数(贫血),缺乏能量(疲乏),肌肉骨骼痛,瘀伤,恶心,上呼吸道感染,和皮疹。卫生保健专业人员应告知患者对出血,感染,异常心跳(房颤)的风险,发生新癌症(第二个原发恶性病),治疗后代谢障碍(肿瘤溶解综合症),和对伴随Imbruvica使用对胚胎毒性效应(胚胎-胎儿毒性)。
FDA授权Imbruvica对WM 突破治疗指定,优先审评,和孤儿产品指定因为公司通过初步临床证据证实药物可能提供超过可得到治疗实质上改善;在递交申请时分别有潜力,将在一种严重情况治疗中显著改善安全性或有效性;和药物意向治疗罕见疾病。
产品的新使用正在被批准超过其处方要用户收费目标日期2015年4月17日,即FDA计划完成药物申请评审目标日期,提早2个月。
Imbruvica由总部在加州Sunnyvale的Pharmacyclics和总部在滨州Horsham Janssen生物技术公司共同上市。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use IMBRUVICA safely and effectively. See full prescribing information for IMBRUVICA.
IMBRUVICA®(ibrutinib) capsules, for oral use
Initial U.S. Approval: 2013
RECENT MAJOR CHANGES

Indications and Usage (1.2, 1.3) 5/2016
Dosage and Administration (2.2) 5/2016
Warnings and Precautions (5) 3/2016
INDICATIONS AND USAGE
IMBRUVICA is a kinase inhibitor indicated for the treatment of patients with:
Mantle cell lymphoma (MCL) who have received at least one prior therapy (1.1).
Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) (1.2).
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion (1.3).
Waldenström's macroglobulinemia (WM) (1.4).
DOSAGE AND ADMINISTRATION
MCL: 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2).
CLL/SLL and WM: 420 mg taken orally once daily (three 140 mg capsules once daily) (2.2).
Capsules should be taken orally with a glass of water. Do not open, break, or chew the capsules (2.1).
DOSAGE FORMS AND STRENGTHS
Capsule: 140 mg (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Hemorrhage: Monitor for bleeding and manage (5.1).
Infections: Monitor patients for fever and infections, evaluate promptly, and treat (5.2).
Cytopenias: Check complete blood counts monthly (5.3).
Atrial Fibrillation: Monitor for atrial fibrillation and manage (5.4).
Hypertension: Monitor blood pressure and treat (5.5).
Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas (5.6).
Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions. Monitor and treat for TLS (5.7).
Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to avoid pregnancy while taking the drug and for 1 month after cessation of therapy. Advise men to avoid fathering a child during the same time period (5.8, 8.3).
ADVERSE REACTIONS
The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia, thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea, bruising, fatigue, hemorrhage, and pyrexia (6).
To report SUSPECTED ADVERSE REACTIONS, contact Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
CYP3A Inhibitors: Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce IMBRUVICA dose (2.4, 7.1).
CYP3A Inducers: Avoid co-administration with strong CYP3A inducers (7.2).
USE IN SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose (2.5, 8.6).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 6/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Mantle Cell Lymphoma
IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1)].
1.2 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) [see Clinical Studies (14.2)].
1.3 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion [see Clinical Studies (14.2)].
1.4 Waldenström's Macroglobulinemia
IMBRUVICA is indicated for the treatment of patients with Waldenström's macroglobulinemia (WM) [see Clinical Studies (14.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Guidelines
Administer IMBRUVICA orally once daily at approximately the same time each day. Swallow the capsules whole with water. Do not open, break, or chew the capsules.
2.2 Dosage
Mantle Cell Lymphoma
The recommended dose of IMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström's Macroglobulinemia
The recommended dose of IMBRUVICA for CLL/SLL and WM is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.
The recommended dose of IMBRUVICA for CLL/SLL when used in combination with bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.
2.3 Dose Modifications for Adverse Reactions
Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological toxicities, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue IMBRUVICA.
Recommended dose modifications are described below:

Toxicity Occurrence MCL Dose Modification After Recovery
Starting Dose = 560 mg
CLL/SLL and WM Dose Modification After Recovery
Starting Dose = 420 mg
First Restart at 560 mg daily Restart at 420 mg daily
Second Restart at 420 mg daily Restart at 280 mg daily
Third Restart at 280 mg daily Restart at 140 mg daily
Fourth Discontinue IMBRUVICA Discontinue IMBRUVICA
2.4 Dose Modifications for Use with CYP3A Inhibitors
Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.
Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and antibiotics) consider interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer needed [see Drug Interactions (7.1)].
Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, and ciprofloxacin) [see Drug Interactions (7.1)].
Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of IMBRUVICA toxicity.
2.5 Dose Modifications for Use in Hepatic Impairment
For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg daily (one capsule). Avoid the use of IMBRUVICA in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.6 Missed Dose
If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra capsules of IMBRUVICA should not be taken to make up for the missed dose.
3 DOSAGE FORMS AND STRENGTHS
140 mg capsules
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Hemorrhage
Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
The mechanism for the bleeding events is not well understood.
IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].
5.2 Infections
Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients [see Adverse Reactions (6.1), (6.2)]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.
5.3 Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA.
Monitor complete blood counts monthly.
5.4 Atrial Fibrillation
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage and Administration (2.3)].
5.5 Hypertension
Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.
5.6 Second Primary Malignancies
Other malignancies (range, 5 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 13%).
5.7 Tumor Lysis Syndrome
Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
5.8 Embryo-Fetal Toxicity
Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryofetal toxicity including malformations at exposures that were 2-20 times higher than those reported in patients with MCL, CLL/SLL or WM. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. 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 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)]
Atrial Fibrillation [see Warnings and Precautions (5.4)]
Hypertension [see Warnings and Precautions (5.5)]
Second Primary Malignancies [see Warnings and Precautions (5.6)]
Tumor Lysis Syndrome [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.
Mantle Cell Lymphoma
The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.
The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2).
The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.
Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.
Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)

Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%)
Gastrointestinal disorders Diarrhea 51 5
Nausea 31 0
Constipation 25 0
Abdominal pain 24 5
Vomiting 23 0
Stomatitis 17 1
Dyspepsia 11 0
Infections and infestations Upper respiratory tract infection 34 0
Urinary tract infection 14 3
Pneumonia 14 7
Skin infections 14 5
Sinusitis 13 1
General disorders and administration site conditions Fatigue 41 5
Peripheral edema 35 3
Pyrexia 18 1
Asthenia 14 3
Skin and subcutaneous tissue disorders Bruising 30 0
Rash 25 3
Petechiae 11 0
Musculoskeletal and connective tissue disorders Musculoskeletal pain 37 1
Muscle spasms 14 0
Arthralgia 11 0
Respiratory, thoracic and mediastinal disorders Dyspnea 27 4
Cough 19 0
Epistaxis 11 0
Metabolism and nutrition disorders Decreased appetite 21 2
Dehydration 12 4
Nervous system disorders Dizziness 14 0
Headache 13 0
Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

Percent of Patients (N=111)
All Grades (%) Grade 3 or 4 (%)

 

Platelets Decreased 57 17
Neutrophils Decreased 47 29
Hemoglobin Decreased 41 9
Based on laboratory measurements and adverse reactions
Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.
Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.
Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
The data described below reflect exposure in one single-arm, open-label clinical trial and three randomized controlled clinical trials in patients with CLL/SLL (n=1278 total and n=668 patients exposed to IMBRUVICA). Study 1 included 51 patients with previously treated CLL/SLL, Study 2 included 391 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab, Study 3 included 269 randomized patients 65 years or older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or chlorambucil and Study 4 included 578 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab.
The most commonly occurring adverse reactions in Studies 1, 2, 3 and 4 in patients with CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10 percent of patients receiving IMBRUVICA in Studies 1, 2, 3 and 4 discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients.
Study 1
Adverse reactions and laboratory abnormalities from the CLL/SLL trial (N=51) using single agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4.
Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1 

Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%)

 

Gastrointestinal disorders Diarrhea 59 4
Constipation 22 2
Nausea 20 2
Stomatitis 20 0
Vomiting 18 2
Abdominal pain 14 0
Dyspepsia 12 0
Infections and infestations Upper respiratory tract infection 47 2
Sinusitis 22 6
Skin infection 16 6
Pneumonia 12 10
Urinary tract infection 12 2
General disorders and administration site conditions Fatigue 33 6
Pyrexia 24 2
Peripheral edema 22 0
Asthenia 14 6
Chills 12 0
Skin and subcutaneous tissue disorders Bruising 51 2
Rash 25 0
Petechiae 16 0
Respiratory, thoracic and mediastinal disorders Cough 22 0
Oropharyngeal pain 14 0
Dyspnea 12 0
Musculoskeletal and connective tissue disorders Musculoskeletal pain 25 6
Arthralgia 24 0
Muscle spasms 18 2
Nervous system disorders Dizziness 20 0
Headache 18 2
Metabolism and nutrition disorders Decreased appetite 16 2
Neoplasms benign, malignant, unspecified Second malignancies* 12* 0
Vascular disorders Hypertension 16 8
One patient death due to histiocytic sarcoma.
Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL/SLL (N=51) in Study 1

Percent of Patients (N=51)
All Grades (%) Grade 3 or 4 (%)
Platelets Decreased 69 12
Neutrophils Decreased 53 26
Hemoglobin Decreased 43 0
Based on laboratory measurements per IWCLL criteria and adverse reactions.
Study 2
Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2 in patients with previously treated CLL/SLL.
Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients in Study 2 

IMBRUVICA
(N=195)
Ofatumumab
(N=191)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Subjects with multiple events for a given ADR term are counted once only for each ADR term.
The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.

 

Gastrointestinal disorders
  Diarrhea 48 4 18 2
  Nausea 26 2 18 0
  Stomatitis* 17 1 6 1
  Constipation 15 0 9 0
  Vomiting 14 0 6 1
General disorders and administration site conditions
  Pyrexia 24 2 15 1
Infections and infestations
  Upper respiratory tract infection 16 1 11 2
  Pneumonia* 15 10 13 9
  Sinusitis* 11 1 6 0
  Urinary tract infection 10 4 5 1
Skin and subcutaneous tissue disorders
  Rash 24 3 13 0
  Petechiae 14 0 1 0
  Bruising 12 0 1 0
Musculoskeletal and connective tissue disorders
  Musculoskeletal Pain* 28 2 18 1
  Arthralgia 17 1 7 0
Nervous system disorders
  Headache 14 1 6 0
  Dizziness 11 0 5 0
Injury, poisoning and procedural complications
  Contusion 11 0 3 0
Eye disorders
  Vision blurred 10 0 3 0
Includes multiple ADR terms 
Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)

 

Neutrophils Decreased 51 23 57 26
Platelets Decreased 52 5 45 10
Hemoglobin Decreased 36 0 21 0
Based on laboratory measurements per IWCLL criteria.
Study 3
Adverse reactions described below in Table 7 reflect exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in Study 3.
Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients in Study 3 

IMBRUVICA
(N=135)
Chlorambucil
(N=132)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Subjects with multiple events for a given ADR term are counted once only for each ADR term.
The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
Gastrointestinal disorders
  Diarrhea 42 4 17 0
  Stomatitis 14 1 4 1
Musculoskeletal and connective tissue disorders
  Musculoskeletal pain 36 4 20 0
  Arthralgia 16 1 7 1
  Muscle spasms 11 0 5 0
Eye Disorders
  Dry eye 17 0 5 0
  Lacrimation increased 13 0 6 0
  Vision blurred 13 0 8 0
  Visual acuity reduced 11 0 2 0
Skin and subcutaneous tissue disorders
  Rash 21 4 12 2
  Bruising 19 0 7 0
Infections and infestations
  Skin infection 15 2 3 1
  Pneumonia 14 8 7 4
  Urinary tract infections 10 1 8 1
Respiratory, thoracic and mediastinal disorders
  Cough 22 0 15 0
General disorders and administration site conditions
  Peripheral edema 19 1 9 0
  Pyrexia 17 0 14 2
Vascular Disorders
  Hypertension 14 4 1 0
Nervous System Disorders
Includes multiple ADR terms 
Study 4
Adverse reactions described below in Table 8 reflect exposure to IMBRUVICA + BR with a median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in Study 4 in patients with previously treated CLL/SLL.
Table 8: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the IMBRUVICA Arm in Patients in Study 4 

Ibrutinib + BR
(N=287)
Placebo + BR
(N=287)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
<1 used for frequency above 0 and below 0.5%

 

Blood and lymphatic system disorders
  Neutropenia 66 61 60 55
  Thrombocytopenia 34 16 26 16
Skin and subcutaneous tissue disorders
  Rash 32 4 25 1
  Bruising 20 <1 8 <1
Gastrointestinal disorders
  Diarrhea 36 2 23 1
  Abdominal Pain 12 1 8 <1
Musculoskeletal and connective tissue disorders
  Musculoskeletal pain 29 2 20 0
  Muscle spasms 12 <1 5 0
General disorders and administration site conditions
  Pyrexia 25 4 22 2
Vascular Disorders
  Hemorrhage 19 2 9 1
  Hypertension 11 5 5 2
Infections and infestations
  Bronchitis 13 2 10 3
  Skin infection 10 3 6 2
Metabolism and nutrition disorders
  Hyperuricemia 10 2 6 0
Includes multiple ADR terms 
Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo +BR.
Waldenström's Macroglobulinemia
The data described below reflect exposure to IMBRUVICA in an open-label clinical trial that included 63 patients with previously treated WM.
The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.
Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients.
Adverse reactions and laboratory abnormalities described below in Tables 9 and 10 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.

Table 9: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström's Macroglobulinemia (N=63)

Body System Adverse Reaction All Grades
(%)
Grade 3 or 4
(%)
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
Gastrointestinal disorders Diarrhea 37 0
Nausea 21 0
Stomatitis 16 0
Gastroesophageal reflux disease 13 0
Skin and subcutaneous tissue disorders Rash 22 0
Bruising 16 0
Pruritus 11 0
General disorders and administrative site conditions Fatigue 21 0
Musculoskeletal and connective tissue disorders Muscle spasms 21 0
Arthropathy 13 0
Infections and infestations Upper respiratory tract infection 19 0
Sinusitis 19 0
Pneumonia 14 6
Skin infection* 14 2
Respiratory, thoracic and mediastinal disorders Epistaxis 19 0
Cough 13 0
Nervous system disorders Dizziness 14 0
Headache 13 0
Neoplasms benign, malignant, and unspecified (including cysts and polyps) Skin cancer* 11 0
Includes multiple ADR terms.
Table 10: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)

Percent of Patients (N=63)
All Grades (%) Grade 3 or 4 (%)
Platelets Decreased 43 13
Neutrophils Decreased 44 19
Hemoglobin Decreased 13 8
Based on laboratory measurements.
Additional Important Adverse Reactions
Diarrhea
Diarrhea of any grade occurred at a rate of 43% (range, 36% to 63%) of patients treated with IMBRUVICA. Grade 2 diarrhea occurred in 9% (range, 3% to 15%) and Grade 3 in 3% (range, 0 to 5%) of patients treated with IMBRUVICA. The median time to first onset of any grade diarrhea was 12 days (range, 0 to 627), of Grade 2 was 37 days (range, 1 to 667) and of Grade 3 was 71days (range, 3 to 627). Of the patients who reported diarrhea, 83% had complete resolution, 1% had partial improvement and 16% had no reported improvement at time of analysis. The median time from onset to resolution or improvement of any grade diarrhea was 5 days (range, 1 to 418), and was similar for Grades 2 and 3. Less than 1% of patients discontinued IMBRUVICA due to diarrhea.
Visual Disturbance
Blurred vision and decreased visual acuity of any grade occurred in 10% of patients treated with IMBRUVICA (9% Grade 1, 2% Grade 2). The median time to first onset was 88 days (range, 1 to 414 days). Of the patients with visual disturbance, 64% had complete resolution and 36% had no reported improvement at time of analysis. The median time from onset to resolution or improvement was 29 days (range, 1 to 281 days).
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of IMBRUVICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hepatobiliary disorders: hepatic failure (includes multiple terms)
Respiratory disorders: interstitial lung disease (includes multiple terms)
Metabolic and nutrition disorders: tumor lysis syndrome [see Warnings & Precautions (5.7)]
Skin and subcutaneous tissue disorders: anaphylactic shock, angioedema, urticaria
7 DRUG INTERACTIONS
7.1 CYP3A Inhibitors
Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A). In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng ∙ hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).
Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4)].
Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].
7.2 CYP3A Inducers
Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and St. John's Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
IMBRUVICA, a kinase inhibitor, can cause fetal harm based on findings from animal studies. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including malformations [see Data]. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Animal Data
Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased resorptions and post-implantation loss. The dose of 80 mg/kg/day in rats is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL/SLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.0 times the exposure (AUC) in patients with MCL and 2.8 times the exposure in patients with CLL/SLL or WM administered the dose of 560 and 420 mg daily, respectively.
8.2 Lactation
Risk Summary
There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.
The development and health benefits of breastfeeding should be considered along with the mother's clinical need for IMBRUVICA and any potential adverse effects on the breastfed child from IMBRUVICA or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating IMBRUVICA therapy.
Contraception
Females
Advise females of reproductive potential to avoid pregnancy while taking IMBRUVICA and for up to 1 month after ending treatment. 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 IMBRUVICA, and for 1 month following the last dose of IMBRUVICA.
8.4 Pediatric Use
The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.
8.5 Geriatric Use
Of the 839 patients in clinical studies of IMBRUVICA, 62% were ≥ 65 years of age, while 21% were ≥75 years of age. No overall differences in effectiveness were observed between younger and older patients. Grade 3 or higher pneumonia occurred more frequently among older patients treated with IMBRUVICA [see Clinical Studies (14.2)].
8.6 Hepatic Impairment
Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function.
The safety of IMBRUVICA has not been evaluated in cancer patients with mild to severe hepatic impairment by Child-Pugh criteria.
Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh class B and C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
8.7 Plasmapheresis
Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.
10 OVERDOSAGE
There is no specific experience in the management of ibrutinib overdose in patients. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive treatment.
11 DESCRIPTION
Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water.
The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:


IMBRUVICA (ibrutinib) capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with "ibr 140 mg" in black ink.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
12.2 Pharmacodynamics
In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg).
In healthy subjects, at a single dose 3 times the maximum recommended dose (1680 mg), ibrutinib did not prolong the QT interval to any clinically relevant extent.
12.3 Pharmacokinetics
Absorption
Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The steady-state AUC (mean ± standard deviation) observed in patients at 560 mg is 953 ± 705 ng∙h/mL and in patients at 420 mg is 680 ± 517 ng∙h/mL. Absolute bioavailability in fasted condition (n = 8) was 2.9% (90% CI = 2.1 – 3.9) and doubled when combined with a meal. Administration with food increased ibrutinib Cmax and AUC by approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after overnight fasting.
Distribution
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL. The volume of distribution (Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10000 L.
Metabolism
Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8.
Elimination
Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, respectively. In line with the high first-pass effect, the apparent oral clearance is approximately 2000 and 1000 L/h in fasted and fed conditions, respectively. The half-life of ibrutinib is 4 to 6 hours.
Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces and none in urine, with the remainder of the dose being metabolites.
Age
In older patients (67 to 81 years), there is a 14% higher ibrutinib exposure predicted. Dose adjustment by age is not warranted.
Gender
Gender does not alter ibrutinib systemic clearance.
Renal Impairment
Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 10% of the dose. Creatinine clearance (CrCL) > 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CrCL < 25 mL/min) or in patients on dialysis.
Hepatic Impairment
Ibrutinib is metabolized in the liver. In a hepatic impairment trial, a single dose of 140 mg of IMBRUVICA was administered in non-cancer subjects. Ibrutinib AUC increased 2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n=6), moderate (n=10) and severe (n=8) hepatic impairment relative to subjects with normal liver function. Ibrutinib Cmax increased 5.2-, 8.8- and 7.0-fold, respectively, in subjects with mild, moderate and severe hepatic impairment relative to subjects with normal liver function [see Use in Specific Populations (8.6)].
Drug Interactions
Coadministration of Ibrutinib with CYP3A Inhibitors
In a sequential design trial of 18 healthy, fasted volunteers, a single dose of 120 mg of IMBRUVICA was administered alone on Day 1 and a single dose of 40 mg of IMBRUVICA was administered on Day 7 in combination with 400 mg of ketoconazole (given daily on Days 4 - 9). Ketoconazole increased ibrutinib dose-normalized Cmax and AUC 29-fold and 24-fold, respectively. Simulations using fasted conditions indicate that moderate CYP3A inhibitors diltiazem and erythromycin may increase AUC of ibrutinib by 5- to 8-fold.
Coadministration of Ibrutinib with CYP3A Inducers
PK data from a dedicated drug interaction trial showed that rifampin (a strong CYP3A inducer) decreases ibrutinib Cmax and AUC by more than 13- and 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of ibrutinib by up to 3-fold.
Coadministration of Ibrutinib with CYP Substrates
In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227 (I/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and the PCI-45227 are weak inducers of CYP450 isoenzymes in vitro.
Coadministration of Ibrutinib with Substrates of Transporters
In vitro studies indicated that ibrutinib is not a substrate of P-gp (p-glycoprotein) or BCRP (breast cancer resistance protein) transporters but is an in vitro inhibitor of P-gp and BCRP. Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1) but may inhibit BCRP. Ibrutinib may have an effect on P-gp or BCRP substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp or BCRP substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their blood concentration.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with ibrutinib.
Ibrutinib 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 mice at doses up to 2000 mg/kg.
Rats were administered oral daily doses of ibrutinib for 4 weeks prior to pairing and during pairing in males and 2 weeks prior to pairing and during pairing in females. Treatment of female rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats continued until end of study. No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED] 16 mg/kg).
14 CLINICAL STUDIES
14.1 Mantle Cell Lymphoma
The safety and efficacy of IMBRUVICA in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 11% with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor ≥ 5 cm, 49% had bone marrow involvement, and 54% had extranodal involvement at screening.
IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to IMBRUVICA are shown in Table 11.
Table 11: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with MCL

Total (N=111)
CI = confidence interval; CR = complete response; PR = partial response; NR = not reached
ORR (%) 65.8
  95% CI (%) (56.2, 74.5)
  CR (%) 17.1
  PR (%) 48.6
Median DOR months (95% CI) 17.5 (15.8, NR)
An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%.
The median time to response was 1.9 months.
Lymphocytosis
Upon initiation of IMBRUVICA, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks of IMBRUVICA therapy and resolves by a median of 8 weeks.
14.2 Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma
The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in one uncontrolled trial and three randomized, controlled trials.
Study 1
An open-label, multi-center trial was conducted in 48 previously treated CLL patients. The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At baseline, 46% of subjects had at least one tumor ≥ 5 cm.
IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.
Study 2
A randomized, multi-center, open-label Phase 3 study of IMBRUVICA versus ofatumumab was conducted in patients with previously treated CLL or SLL. Patients (n=391) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4 additional doses. Fifty seven patients randomized to ofatumumab crossed over following progression to receive IMBRUVICA. The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion.
Efficacy results for Study 2 are shown in Table 12 and the Kaplan-Meier curves for PFS, assessed by independent review committee (IRC) according to IWCLL criteria, and OS are shown in Figures 1 and 2, respectively.
Table 12: Efficacy Results in Study 2

Endpoint IMBRUVICA
N=195
Ofatumumab
N=196
CI = confidence interval; HR = hazard ratio; NR = not reached
Progression Free Survival*
Number of events (%) 35 (17.9) 111 (56.6)
  Disease progression 26 93
  Death events 9 18
  Median (95% CI), months NR 8.1 (7.2, 8.3)
  HR (95% CI) 0.22 (0.15, 0.32)
Overall Survival
  Number of deaths (%) 16 (8.2) 33 (16.8)
  HR (95% CI) 0.43 (0.24, 0.79)
Overall Response Rate 42.6% 4.1%
IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
Median OS not reached for either arm 
Figure 1: Kaplan-Meier Curve of Progression Free Survival (ITT Population) in Study 2


Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Study 2


CLL/SLL with 17p deletion (del 17p CLL/SLL) in Study 2
Study 2 included 127 patients with del 17p CLL/SLL. The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. PFS and ORR were assessed by IRC. Efficacy results for del 17p CLL/SLL are shown in Table 13.
Table 13: Efficacy Results in Patients with del 17p CLL/SLL in Study 2

Endpoint IMBRUVICA
N=63
Ofatumumab
N=64
CI = confidence interval; HR = hazard ratio; NR = not reached
Progression Free Survival*
Number of events (%) 16 (25.4) 38 (59.4)
  Disease progression 12 31
  Death events 4 7
  Median (95% CI), months NR 5.8 (5.3, 7.9)
  HR (95% CI) 0.25 (0.14, 0.45)
Overall Response Rate 47.6% 4.7%
IRC evaluated. All partial responses achieved; none of the patients achieved a complete response. 
Study 3
A randomized, multi-center, open-label study of IMBRUVICA versus chlorambucil was conducted in patients with treatment naïve CLL or SLL who were 65 years of age or older. Patients (n = 269) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability.
The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an ECOG performance status of 2. The trial enrolled 249 patients with CLL and 20 patients with SLL. At baseline, 20% of patients had 11q deletion. The most common reasons for initiating CLL therapy include: progressive marrow failure demonstrated by anemia and/or thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).
With a median follow-up of 28.1 months, there were 32 observed death events [11 (8.1%) and 21 (15.8%) in IMBRUVICA and chlorambucil treatment arms, respectively]. With 41% of patients switching from chlorambucil to IMBRUVICA, the overall survival analysis in the ITT patient population resulted in a statistically significant HR of 0.44 [95% CI (0.21, 0.92)] and 2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)] in the IMBRUVICA and chlorambucil arms, respectively.
Efficacy results for Study 3 are shown in Table 14 and the Kaplan-Meier curve for PFS, assessed by independent review committee (IRC) according to IWCLL criteria is shown in Figure 3.
Table 14: Efficacy Results in Study 3

Endpoint IMBRUVICA
N=136
Chlorambucil
N=133
Progression Free Survival
Number of events (%) 15 (11.0) 64 (48.1)
  Disease progression 12 57
  Death events 3 7
    Median (95% CI), months NR 18.9 (14.1, 22.0)
    HR (95% CI) 0.16 (0.09, 0.28)
Overall Response Rate (CR + PR) 82.4% 35.3%
    P-value <0.0001
IRC evaluated; Five subjects (3.7%) in the IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved complete response HR = hazard ratio; NR = not reached
Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Study 3


Study 4
A randomized, multicenter, double-blinded Phase 3 study of IMBRUVICA in combination with bendamustine and rituximab (BR) versus placebo + BR was conducted in patients with previously treated CLL or SLL. Patients (n = 578) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2 and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day 1, and 500 mg/m2 Cycles 2 through 6, Day 1.
The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, 56% of patients had at least one tumor ≥ 5 cm and 26% presented with del11q.
Efficacy results for Study 4 are shown in Table 15 and the Kaplan-Meier curves for PFS are shown in Figure 4.
Table 15: Efficacy Results in Study 4

Endpoint IMBRUVICA + BR
N=289
Placebo + BR
N=289
BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio
Progression Free Survival*
  Number of events (%) 56 (19.4) 183 (63.3)
  Median (95% CI), months Not reached 13.3 (11.3, 13.9)
  HR (95% CI) 0.20 (0.15, 0.28)
Overall Response Rate 82.7% 67.8%
IRC evaluated, Twenty four subjects (8.3%) in the IMBRUVICA + BR arm and six subjects (2.1%) in the placebo + BR arm achieved complete response 
Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Study 4


Lymphocytosis
Upon initiation of IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of patients in the CLL studies. The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks). When IMBRUVICA was administered with chemoimmunotherapy, lymphocytosis was 7% with IMBRUVICA + BR versus 6% with placebo + BR.
14.3 Waldenström's Macroglobulinemia
The safety and efficacy of IMBRUVICA in WM were evaluated in an open-label, multi-center, single-arm trial of 63 previously treated patients. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).
IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an Independent Review Committee (IRC) using criteria adopted from the International Workshop of Waldenström's Macroglobulinemia. Responses, defined as partial response or better, per IRC are shown in Table 16.
Table 16: Overall Response Rate (ORR) and Duration of Response (DOR) Based on IRC Assessment in Patients with WM

Total (N=63)
CI = confidence interval; NR = not reached
Response rate (CR+VGPR+PR), (%) 61.9
  95% CI (%) (48.8, 73.9)
  Complete Response (CR) 0
  Very Good Partial Response (VGPR), (%) 11.1
  Partial Response (PR), (%) 50.8
Median duration of response, months (range) NR (2.8+, 18.8+)
The median time to response was 1.2 months (range, 0.7-13.4 months).
16 HOW SUPPLIED/STORAGE AND HANDLING
The white opaque 140 mg capsules marked with "ibr 140 mg" in black ink are available in white HDPE bottles with a child-resistant closure:
90 capsules per bottle: NDC 57962-140-09
120 capsules per bottle: NDC 57962-140-12
Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F to 86°F). Retain in original package until dispensing.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dfd0279-ff17-4ea9-89be-9803c71bab44
强生抗癌药Imbruvica新适应症获FDA批准
2014年2月13日,抗癌药Imbruvica(ibrutinib胶囊)获FDA批准,用于既往接受过至少一次治疗的慢性淋巴细胞白血病(CLL)患者的治疗。Imbruvica已于2013年11月获FDA批准,用于既往接受过至少一次来那度胺或其他药物治疗的套细胞淋巴瘤(MCL)患者的治疗。这2个适应症的获批,均基于整体缓解率(ORR)数据,该药对存活或疾病相关症状改善的数据尚未建立。
Imbruvica是首个每日一次、单一制剂、口服布鲁顿酪氨酸激酶(BTK)抑制剂,由强生和Pharmacyclics公司联合开发和商业化。此前,Imbruvica治疗CLL和MCL适应症均已授予优先审查资格,并根据FDA的加速批准程序批准。同时,Imbruvica也是FDA授予突破性疗法认定并获批的首批药物之一。
突破性疗法称号是2012年FDA安全和创新法案中制定的部分内容,目的是帮助加快用于严重致命疾病的潜在新药的开发进度,这些药物的临床前研究就已显示比现有的治疗药物在一项或多项临床指标上具有明显改进。
慢性淋巴细胞白血病(Chronic Lymphocytic Leukemia,CLL)是一种淋巴细胞血液癌症,在美国,CLL是一种罕见病。据估计,每年有1.6万人确诊为CLL,有近4600人不幸死于CLL。
Imbruvica是布鲁顿酪氨酸激酶(BTK)抑制剂,通过阻断BTK抑制肿瘤细胞的复制和转移,从而起到抗癌作用。
第6个适应症!FDA批准艾伯维突破性药物Imbruvica治疗小淋巴细胞性淋巴瘤(SLL)
美国制药巨头艾伯维(AbbVie)近日宣布,美国食品和药物管理局(FDA)已更新突破性抗癌药Imbruvica(ibrutinib)的处方信息(Prescribing Information,PI),纳入2项III期临床研究的新数据,这些研究支持了Imbruvica扩大应用于慢性淋巴细胞白血病(CLL)和小淋巴细胞性淋巴瘤(SLL)的治疗。
此次标签更新纳入了Imbruvica一线治疗CLL/SLL的III期RESONATE-2研究的总生存(OS)数据,以及Imbruvica联合苯达莫司汀+利妥昔单抗(bendamustine+rituximab,BR)三联疗法治疗复发性/难治性CLL/SLL的III期HELIOS研究的疗效和安全性数据。
与此同时,FDA批准了Imbruvica的一个新适应症,即Imbruvica作为单药或联合苯达莫司汀+利妥昔单抗(BR)用于伴有或不伴有染色体17p删除突变(del 17p)的SLL患者,这也是Imbruvica在美国获批的第6个适应症。今年3月,FDA根据RESONATE-2研究数据批准Imbruvica的第5个适应症,即一线治疗CLL。而在美国,Imbruvica此前已获批用于:复发性或难治性套细胞淋巴瘤(MCL)、经治慢性淋巴细胞白血病(CLL)、携带17p删除突变的CLL、Waldenstrom巨球蛋白血症(WM)。
RESONATE-2研究:
RESONATE-2研究是一项随机、多中心、开放标签III期临床研究,在269例初治(既往未接受治疗)慢性淋巴细胞白血病(CLL)或小淋巴细胞淋巴瘤(SLL)老年患者(年龄≥65岁)中开展,调查了Imbruvica相对于苯丁酸氮芥(chlorambucil)化疗的疗效和安全性。Imbruvica治疗组,日服一次420mg剂量Imbruvica,直至病情进展或不可接受的副作用。苯丁酸氮芥治疗组,服用苯丁酸氮芥,28天一周期,每个周期的第1、15天服药,共计治疗12周期;第1周期苯丁酸氮芥起始剂量0.5mg/kg,根据耐受性在第2周期剂量升高0.1mg/kg至最大剂量0.8mg/kg。
根据独立审查委员会(IRC)的评估结果,与苯丁酸氮芥相比,Imbruvica显著延长了无进展生存期(中位PFS:未达到 vs 18.9个月),疾病进展或死亡风险显著降低84%,达到了研究的主要终点。此外,Imbruvica治疗组总生存期(OS,关键次要终点)显著延长,24个月生存率高达98%,苯丁酸氮芥治疗组为85%(HR:0.16,95%CI:0.05-0.56)。
除了现有的PFS及OS积极数据外,一项补充总生存分析纳入了苯丁酸氮芥治疗组41%的患者,这些患者接受苯丁酸氮芥治疗后病情进展,转向Imbruvica治疗。分析显示,中位随访28.1个月,这些患者的死亡风险显著降低56%,数据具有统计学显著性。
HELIOS研究:
HELIOS研究是一项随机、多中心、双盲III期临床研究,纳入了578例接受过至少一次系统疗法的CLL/SLL患者。研究中,患者随机分配至Imbruvica(每日一次)或安慰剂,同时联合苯达莫司汀+利妥昔单抗(bendamustine+rituximab,BR)治疗6个周期,直至病情进展或不可接受的副作用。数据显示,该研究达到了无进展生存期的主要终点。与安慰剂+BR治疗组相比,Imbruvica+BR三联疗法治疗组疾病进展或死亡风险显著降低80%(中位PFS:未达到 vs 13.3个月)。
Imbruvica(ibrutinib)是一种首创的口服布鲁顿酪氨酸激酶(BTK)抑制剂,通过抑制肿瘤细胞复制和转移所需的BTK发挥抗癌作用。Imbruvica能够阻断介导恶性B细胞不可控地增殖和扩散的信号通路,帮助杀死并降低癌细胞数量,延缓癌症的恶化。在临床试验中,Imbruvica单药及组合疗法针对广泛类型的血液系统恶性肿瘤展现出了强大的疗效,包括慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)、Waldenstrom巨球蛋白血症(WM)、弥漫性大B细胞淋巴癌(CLBCL)、滤泡性淋巴瘤(FL)、多发性骨髓瘤(MM)及边缘区淋巴瘤(MZL)等。

责任编辑:admin


相关文章
白血病新药Blincyto已获欧盟批准用于急性淋巴细胞白血病
FDA批准Imbruvica(依鲁替尼)第6个适应症
欧盟批准Imbruvica为抗癌药的第5个适应症
DARZALEX(daratumumab solution for infusion)
强生抗癌药Darzalex获欧盟批准用于治疗难治性和复发性多发性骨髓瘤
突破性抗癌药venetoclax获欧盟受理上市许可
阿特朱单抗注射液|TECENTRIQ(atezolizumab injection)
TECENTRIQ(atezolizumab injection)
Tecentriq(atezolizumab)注射液
Tecentriq(atezolizumab)注射液为首个治疗膀胱癌
FDA批准Tecentriq(atezolizumab)为治疗膀胱癌新靶向药
 

最新文章

更多

· Cabometyx(cabozantini...
· 乐伐替尼硬胶囊|Kisplyx...
· Casodex(Bicalutamide F...
· 卡莫司汀用于注射|BiCNU...
· Lonsurf(Trifluridine/...
· Yondelis(ET-743,Trabec...
· KYTRIL Tablet(盐酸格拉...
· AKYNZEO(netupitant/pal...
· 依维莫司片|Afinitor(e...
· LENVIMA(lenvatinib cap...

推荐文章

更多

· Cabometyx(cabozantini...
· 乐伐替尼硬胶囊|Kisplyx...
· Casodex(Bicalutamide F...
· 卡莫司汀用于注射|BiCNU...
· Lonsurf(Trifluridine/...
· Yondelis(ET-743,Trabec...
· KYTRIL Tablet(盐酸格拉...
· AKYNZEO(netupitant/pal...
· 依维莫司片|Afinitor(e...
· LENVIMA(lenvatinib cap...

热点文章

更多

· 乐伐替尼硬胶囊|Kisplyx...
· Cabometyx(cabozantini...