英文药名：Imbruvica(Ibrutinib 140mg Capsules)
IMBRUVICA®（依鲁替尼 Ibrutinib）胶囊 供口服使用
第二原发恶性肿瘤：其他恶性肿瘤，发生在患者，包括皮肤癌和癌 - 其他。
胚胎 - 胎儿毒性：能引起胎儿危害。建议的潜在风险女性胎儿和避免怀孕而服用药物和1个月后停止治疗。建议男性不要抚养一个被孩子在萨米时间。
评论患者B细胞恶性肿瘤（MCL，CLL / SLL和WM）为白细胞减少，血小板减少，腹泻，贫血，肌肉骨骼痛，皮疹，恶心，青紫，疲劳，出血，最常见的不良反应（≥20％）发热。
IMBRUVICA® (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia Approval based on data from the Phase 3 RESONATE™-2 trial showing an 84% reduction in the risk of progression or death with IMBRUVICA compared to chlorambucil
- First FDA-approved chemotherapy-free treatment option for first-line CLL patients
- This is the 5th treatment indication for IMBRUVICA
U.S. Food and Drug Administration (FDA) approved IMBRUVICA® (ibrutinib) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).1 The approval is based on data from the randomized, multi-center, open-label Phase 3 RESONATE™-2 (PCYC-1115) trial, which evaluated the use of IMBRUVICA versus chlorambucil in 269 treatment-naïve patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older. The RESONATE-2 data were previously presented at the American Society of Hematology (ASH) Annual Meeting in December 2015 and also simultaneously published in The New England Journal of Medicine. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc.
"This approval represents a significant leap forward for patients diagnosed with CLL who may want to consider an alternative first-line treatment to traditional chemotherapy," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "AbbVie is committed to making significant improvements in the lives of patients with hematologic malignancies and will continue to explore ways to improve treatment options for patients."
The prevalence of CLL is approximately 115,000 patients in the U.S.2 with approximately 15,000 newly diagnosed patients every year.3 CLL is a disease of elderly patients, with an average diagnosis age of 71.3
The National Comprehensive Cancer Network (NCCN) recently published an update to its clinical practice guidelines for non-Hodgkin's lymphomas, granting IMBRUVICA a category 1 recommendation for certain CLL patients, the highest recommendation assigned by the organization. Specifically, NCCN recommends IMBRUVICA as a first-line treatment option for frail CLL patients with significant comorbidities, as well as for CLL patients with or without del 17p or the genetic mutation TP53 who are 70 years or older, or younger patients with significant comorbidities. The NCCN guidelines inform prescribing and reimbursement practices in many institutions in the U.S. and internationally.
"The progression-free survival data seen in these previously untreated CLL patients are strong and encouraging," said Dr. Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX and the RESONATE-2 lead study investigator.* "This is especially important for first-line CLL patients, when considering the safety profile. This treatment represents another option for these patients."
IMBRUVICA is now approved to treat CLL patients regardless of their treatment history (treatment-naïve and previously-treated patients). In addition, IMBRUVICA is approved to treat high-risk CLL patients with del 17p,1 a genetic aberration that occurs when part of chromosome 17, the location of the tumor suppressor gene p53, has been lost or deleted.4
IMBRUVICA significantly prolonged progression-free survival (PFS; primary endpoint) as determined by an Independent Review Committee (IRC), reducing the risk of progression or death by 84% versus chlorambucil (hazard ratio [HR], 0.161 [95% confidence interval: 0.091, 0.283]; median PFS: not reached for IMBRUVICA vs. 18.9 months [95% confidence interval: 14.1, 22.0] for chlorambucil).1 IMBRUVICA was also associated with a significantly higher IRC-assessed overall response rate (ORR: a composite of complete and partial responses; 82.4% vs. 35.3%; P<0.0001) versus chlorambucil.1 Five patients (3.7 percent) in the IMBRUVICA arm achieved a complete response, compared to two patients (1.5 percent) in the chlorambucil arm.1
The safety of IMBRUVICA in this patient population was consistent with previously reported studies. The adverse reactions (AR) reported in the U.S. Prescribing Information reflect exposure to IMBRUVICA with a median duration of 17.4 months versus a median exposure to chlorambucil of 7.1 months: nearly 2.5 times longer exposure for IMBRUVICA. Warnings and Precautions include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, embryo-fetal toxicity and tumor lysis syndrome. The most commonly occurring adverse reactions of all Grades in CLL patients treated with IMBRUVICA in the RESONATE-2 trial (>20%) were diarrhea, musculoskeletal pain, cough and rash.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
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 postsurgery depending upon the type of surgery and the risk of bleeding.
Infections - Fatal and nonfatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Evaluate patients for fever and infections and treat appropriately.
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%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.
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 (eg, 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 dose modification.
Hypertension - Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA® with a median time to onset of 4.5 months (range, 0.03 to 18.40 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA®. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.
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%).
Tumor Lysis Syndrome - Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. 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.
The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 53%, 43%), diarrhea (51%, 48%, 37%), anemia* (41%, 37%, 13%), neutropenia* (47%, 46%, 44%), musculoskeletal pain (37%, 32%†, NA‡), fatigue (41%, 29%, 21%), bruising (30%, 25%†, 16%†), nausea (31%, 24%, 21%), rash (25%, 23%†, 22%†), and upper respiratory tract infection (34%, 19%, 19%).
*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
†Includes multiple ADR terms.
‡Not applicable; no associated ADRs.
The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%). Approximately 4% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.
Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, subdural hematomas, and atrial fibrillation (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.
CYP3A Inhibitors - Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.
CYP3A Inducers - Avoid coadministration with strong CYP3A inducers.
Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose.
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。
Generic Name and Formulations:
Ibrutinib 140mg; caps.
Pharmacyclics and Janssen Biotech
Indications for IMBRUVICA:
Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy. CLL in patients with 17p deletion.
Swallow whole with water. MCL: 560mg once daily. CLL: 420mg once daily. Concomitant moderate CYP3A inhibitors: 140mg once daily. Dose modifications for toxicities: see full labeling.
Bruton’s tyrosine kinase (BTK) inhibitor.
Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly. Periodically monitor for atrial fibrillation (esp. in those with cardiac risk factors, acute infections, history of atrial fibrillation); do ECG if arrhythmic symptoms or new onset dyspnea develop. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Hepatic or renal impairment. Maintain adequate hydration. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.
Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for short-term (≤7days) use of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin); consider interrupting ibrutinib therapy. If concomitant moderate CYP3A inhibitors must be used (eg, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, ciprofloxacin): reduce ibrutinib dose (see Adults). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort); consider alternatives. Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants.
Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, decreased appetite, pyrexia.