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2014年2月13日,抗癌药Imbruvica（ibrutinib胶囊/PCI-32765）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 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) who have received at least one prior therapy (1.2). Chronic lymphocytic leukemia 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 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: 140mg (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Hemorrhage: Monitor for bleeding (5.1). Infections: Monitor patients for fever and infections and evaluate promptly (5.2). Cytopenias: Check complete blood counts monthly (5.3). Atrial Fibrillation: Monitor patients for atrial fibrillation (5.4). Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas (5.5). Tumor Lysis Syndrome (TLS): Monitor patients at risk for TLS (e.g. high tumor burden) (5.6). Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to avoid pregnancy while taking the drug (5.7). ADVERSE REACTIONS The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. (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. (6) 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: Avoid use of IMBRUVICA in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose (8.7). See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 1/2015 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 IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2)]. 1.3 Chronic Lymphocytic Leukemia with 17p deletion IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) 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. Chronic Lymphocytic Leukemia and Waldenström's Macroglobulinemia The recommended dose of IMBRUVICA for CLL and WM is 420 mg (three 140 mg capsules) orally once daily. 2.3 Dose Modifications for Adverse Reactions Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, 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:
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 (8.7) 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 (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. 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 26% of patients. [See Adverse Reactions (6.1)]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly. 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%) occurred in patients treated with 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, 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. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3)]. 5.5 Second Primary Malignancies Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). 5.6 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). 5.7 Embryo-Fetal Toxicity Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. 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)] Second Primary Malignancies [see Warnings and Precautions (5.5)] Tumor Lysis Syndrome [see Warnings and Precautions (5.6)] 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. 6.1 Clinical Trials Experience 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)
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 The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1 Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1
Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1
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. Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2
Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2
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 7 and 8 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial. Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström's Macroglobulinemia (N=63)
Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)
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. Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. 7 DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. 7.1 CYP3A Inhibitors 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 Pregnancy Category D [see Warnings and Precautions (5.7)]. Risk Summary Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. 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. Animal Data Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral 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 post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL 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 animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. 8.3 Nursing Mothers It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. 8.5 Geriatric Use Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2)]. Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients. 8.6 Renal Impairment Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3)]. 8.7 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 patients with hepatic impairment. 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 classes B and C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. 8.8 Females and Males of Reproductive Potential Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations (8.1)]. 8.9 Plasmapheresis Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required. 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:
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 The safety and efficacy of IMBRUVICA in patients with CLL who have received at least one prior therapy were demonstrated in one uncontrolled trial and one randomized, controlled trial. 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, multicenter, 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. Progression free survival (PFS) as assessed by independent review committee (IRC) according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression. Analysis of overall survival (OS) demonstrated a 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA arm. Efficacy results for Study 2 are shown in Table 10 and the Kaplan-Meier curves for PFS and OS are shown in Figures 1 and 2, respectively. Table 10: Efficacy Results in Study 2
Median OS not reached for either arm IRC evaluated. All partial responses achieved; none of the patients achieved a complete response. Figure 1: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Study 2
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 77% of patients in the CLL study. The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 23 weeks (range 1 – 104+ weeks). 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 12. Table 12: Response Rate and Duration of Response Based on IRC Assessment in Patients with WM
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. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions (5.1)]. Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions (5.2)]. Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions (5.4)]. Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions (5.5)]. Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.6)]. Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions (5.7)]. Inform patients to take IMBRUVICA orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1)]. Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5)]. Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions (6)]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dfd0279-ff17-4ea9-89be-9803c71bab44 FDA批准艾伯维突破性抗癌药Imbruvica一线治疗慢性淋巴细胞白血病（CLL） 2016年3月9日美国FDA已批准突破性抗癌药Imbruvica（ibrutinib）用于慢性淋巴细胞白血病（CLL）患者的一线治疗。此次批准，首次为CLL群体提供了一种无化疗（chemotherapy-free）的一线治疗选择，同时也使得Imbruvica在美国的治疗适应症达到了5个之多。此前，Imbruvica已获FDA批准用于：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）。 在美国，大约有11.5万例慢性淋巴细胞白血病（CLL）患者，每年新增约1.5万例。CLL患者多为老年患者，平均诊断年龄为71岁。此次批准，标志着CLL临床治疗的一个重大飞跃，将为CLL群体提供除传统化疗之外的一种新的一线治疗选择。 Imbruvica最初由美国医药巨头强生（JNJ）与Pharmacyclics公司共同开发，之后，强生在去年3月计划以超过170亿美元收购Pharmacyclics，但却被艾伯维以210亿美元成功抢婚。通过此次收购，艾伯维获得了这款“钱”途无量且与自身肿瘤学管线完美互补的突破性抗癌药Imbruvica在美国市场的销售权，该药在美国监管方面先后获得了突破性药物资格、优先审查资格、加速批准及孤儿药地位。 去年，Imbruvica在美国已获批的4个适应症，为艾伯维带来了近10亿美元的收入。业界对Imbruvica的前景也十分看好，预计该药的年销售峰值将突破50亿美元。 此次，Imbruvica一线治疗CLL新适应症的获批，是基于一项随机、多中心、开放标签III期RESONATE-2（PCYC-115）临床研究的数据，该研究在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）的疗效和安全性。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，与苯丁酸氮芥相比，Imbruvica也与显著更高的IRC评估的总体缓解率相关（ORR：完全缓解+部分缓解，82.4% vs 35.3%，p＜0.0001）。Imbruvica治疗组有5例（占3.7%）实现完全缓解，苯丁酸氮芥治疗组有2例（占1.5%）实现完全缓解。 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。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
