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依鲁替尼胶囊|IMBRUVICA(ibrutinib capsules)

2014-05-27 03:25:02  作者:新特药房  来源:互联网  浏览次数:961  文字大小:【】【】【
简介:近日,FDA批准Imbruvica (ibrutinib)新适应症,用于之前至少接受过一种药物治疗的慢性淋巴细胞白血病(CLL)患者。CLL是一种罕见的血液及骨髓疾病,该疾病通常会随着时间的推移缓慢恶化,引起B淋巴细胞逐 ...

IMBRUVICA (ibrutinib) capsule
[Pharmacyclics, Inc]
商品名:Imbruvica 
通用名:ibrutinib 
中文名:依鲁替尼
审批分类:突破性药物+优先审评+加速批准+孤儿药
药企:Pharmacyclics/Janssen Biotech Inc.
药品介绍
依鲁替尼IMBRUVICA(ibrutinib)获准用于治疗慢性淋巴细胞白血病

美国FDA于2014年2月12日宣布,扩大批准Imbruvica(ibrutinib,依鲁替尼)用途,将其用于先前接受过至少一种药物的慢性淋巴细胞白血病(CLL)患者。
CLL是一种罕见的血液和骨髓疾病,通常此症随着时间的推移慢慢恶化,引起体内称为B淋巴细胞,或B细胞的白血细胞逐渐增加。美国国家癌症研究所估计,2013年有15680名美国人被诊断出罹患此症,以及4580因此死亡。
Imbruvica通过阻断一种允许癌细胞生长和分裂的酶产生效果。2013年11月, Imbruvica获得FDA加速批准,治疗套细胞淋巴瘤(一种罕见的侵袭性血癌),患者(之前他们至少接受过一种药物治疗)。“今天的获准为尽管已经接受先前的治疗,但病情仍然恶化的CLL患者提供了新的重要选择,”FDA的药品评价和研究中心血液学和肿瘤产品办公室主任Richard Pazdur博士指出。“FDA按照加速审批程序完成了Imbruvica这一新适应症的审查。”
根据加速审批程序,FDA可根据能合理预测临床益处的一种替代或中间终点指标批准新药。获得加速批准的药物通常需履行一份协议,进行验证性试验证实和说明其临床益处。Imbruvica用于CLL也获得优先审查和罕用药认定,因为它对一种严重疾病的治疗中被证实疗效和安全性显著改善,并且是被用于治疗一种罕见疾病。
FDA批准Imbruvica用于CLL治疗的加速批准是根据一项48名先前作过治疗的患者参与的临床研究结果。平均而言,这些参与者在参与临床研究之前6.7年被确诊为白血病,并接受过4种药物。所有研究对象接受Imbruvica,口服420毫克剂量,直至出现不可接受的毒性或疾病恶化。结果表明,近58%参与者治疗后癌症萎缩(整体应答率)。在研究时,应答的持续时间从5.6至24.2个月。在存活或疾病相关症状改善数据尚未确立。
在临床研究中观察到的最常见副作用包括血液血小板减少、腹泻、紫癜、抗感染白细胞(中性粒细胞)减少、红血细胞下降(贫血)、上呼吸道感染、疲劳、骨骼肌肉疼痛、皮疹、发热、便秘、组织肿胀(外周性水肿)、关节痛、恶心、口腔溃疡(口腔炎)、鼻窦感染和头晕。
Imbruvica由总部位于加州Sunnyvale的Pharmacyclics公司生产。
IMBRUVICA(ibrutinib)胶囊获FDA批准为口服使用
美国初次批准:
2013
适应证和用途
IMBRUVICA是一个激酶抑制剂适用为的治疗曾接受至少1次既往治疗有套细胞淋巴瘤(MCL) 患者。
这个适应证是根据总缓解率。尚未确定生存或疾病相关症状改善.
剂量和给药方法
560 mg口服每天1次(4粒140 mg胶囊每天1次)。
应用一杯水口服胶囊。 不要打开,破裂,或咀嚼胶囊.
剂型和规格
胶囊:140mg
禁忌证
无。
警告和注意事项
(1)出血:对出血监视。
(2)感染:监视对发热和感染患者和及时评价。
(3)骨髓抑制:每月检查全血细胞计数.
(4)肾毒性:监视肾功能和保持水化.
(5)第二个原发恶性肿瘤:患者中曾发生其他恶性肿瘤,包括皮肤癌,和其他癌.
(6)胚胎-胎儿毒性:可致胎儿危害。忠告妇女对胎儿潜在风险当妊娠时避免服.
不良反应
最常见不良反应(≥20%) in患者with MCL were 血小板减少,腹泻,中性粒细胞减少,贫血,疲乏,肌肉骨骼痛,外周性水肿,上呼吸道感染,恶心,瘀伤,呼吸困难,便秘,皮疹,腹痛,呕吐和食欲减低.

FULL PRESCRIBING INFORMATION

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. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [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. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.2)].

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

The recommended dose of IMBRUVICA for CLL 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 for these toxicities are described below:

Toxicity Occurrence MCL Dose Modification After Recovery
Starting Dose = 560 mg
CLL 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, grapefruit products 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 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

Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

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. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions (6.1) and (6.2)]. Monitor patients for fever and infections and evaluate promptly.

5.3 Myelosuppression

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL.

Monitor complete blood counts monthly.

5.4 Renal Toxicity

Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

5.5 Second Primary Malignancies

Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

5.6 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, 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)]
  • Myelosuppression [see Warnings and Precautions (5.3)]
  • Renal Toxicity [see Warnings and Precautions (5.4)]
  • Second Primary Malignancies [see Warnings and Precautions (5.5)]

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 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.

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 Mantle Cell Lymphoma (N=111)
System Organ Class Preferred Term 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 administrative 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 (%)
*
Based on laboratory measurements and adverse reactions
Platelets Decreased 57 17
Neutrophils Decreased 47 29
Hemoglobin Decreased 41 9

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.

6.2 Chronic Lymphocytic Leukemia

The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48)
System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%)
*
One patient death due to histiocytic sarcoma.
Gastrointestinal disorders Diarrhea 63 4
Constipation 23 2
Nausea 21 2
Stomatitis 21 0
Vomiting 19 2
Abdominal pain 15 0
Dyspepsia 13 0
Infections and infestations Upper respiratory tract infection 48 2
Sinusitis 21 6
Skin infection 17 6
Pneumonia 10 8
Urinary tract infection 10 0
General disorders and administrative site conditions Fatigue 31 4
Pyrexia 25 2
Peripheral edema 23 0
Asthenia 13 4
Chills 13 0
Skin and subcutaneous tissue disorders Bruising 54 2
Rash 27 0
Petechiae 17 0
Respiratory, thoracic and mediastinal disorders Cough 19 0
Oropharyngeal pain 15 0
Dyspnea 10 0
Musculoskeletal and connective tissue disorders Musculoskeletal pain 27 6
Arthralgia 23 0
Muscle spasms 19 2
Nervous system disorders Dizziness 21 0
Headache 19 2
Peripheral neuropathy 10 0
Metabolism and nutrition disorders Decreased appetite 17 2
Neoplasms benign, malignant, unspecified Second malignancies* 10* 0
Injury, poisoning and procedural complications Laceration 10 2
Psychiatric disorders Anxiety 10 0
Insomnia 10 0
Vascular disorders Hypertension 17 8
Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48)
Percent of Patients (N=48)
All Grades (%) Grade 3 or 4 (%)
*
Based on laboratory measurements per IWCLL criteria and adverse reactions
Platelets Decreased 71 10
Neutrophils Decreased 54 27
Hemoglobin Decreased 44 0

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients.

Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL.

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 strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold.

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 (5.6)].

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 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 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger 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 and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 × upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see 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)].

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).

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. Administration with food increases ibrutinib exposure approximately 2-fold compared with administration 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 apparent volume of distribution at steady state (Vd,ss/F) is 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

Apparent clearance (CL/F) is approximately 1000 L/h. 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

Age (37 to 84 years) does not alter ibrutinib systemic clearance.

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 > 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis.

Hepatic Impairment

Ibrutinib is metabolized in the liver. No clinical trials have been completed in subjects with impaired hepatic function. Preliminary PK data from an ongoing trial in subjects with hepatic impairment indicate that ibrutinib exposure is approximately 6-fold higher in subjects (N=3) with moderate hepatic impairment (Child-Pugh B) compared with mean exposures observed in healthy volunteer trials.

Drug Interactions

Coadministration of Ibrutinib with CYP3A Inhibitors

In a sequential design trial of 18 healthy 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 physiologically-based pharmacokinetic (PBPK) models suggested that moderate CYP3A inhibitors (diltiazem and erythromycin) may increase the AUC of ibrutinib 6 to 9-fold in fasted condition.

Coadministration of Ibrutinib with CYP3A Inducers

Preliminary PK data from an ongoing dedicated drug interaction trial and simulations using PBPK indicate that rifampin (a strong CYP3A inducer) can decrease ibrutinib Cmax and AUC by more than 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of ibrutinib 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-glycoprotein (P-gp). Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1). However, it may have an effect on P-gp substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) 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.

Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects on reproductive organs.

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 5.

Table 5: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with Mantle Cell Lymphoma
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

The safety and efficacy of IMBRUVICA in patients with CLL who have received at least one prior therapy were evaluated in an open-label, multi-center trial of 48 previously treated 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.

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).

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.

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) suggestive of infection [see Warnings and Precautions (5.2)].
  • Renal toxicity:
    Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [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)].
  • Embryo-fetal toxicity:
    Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions (5.6)].
  • 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.

Ibrutinib单药治疗对套细胞性淋巴瘤(MCL)或弥漫性大B细胞性淋巴瘤(DLBCL)患者有效
Pharmacyclics生物制药公司(纳斯达克:PCYC)今日宣布2项单独的II期临床实验显示口服ibrutinib单药治疗复发/难治性MCL或DLBCL患者有效。Ibrutinib是一种实验性布鲁顿酪氨酸激酶(Bruton‘s Tyrosine Kinase, BTK)抑制剂。 Pharmacyclics公司资助了这两项研究,并与扬森研发责任有限公司共同开发了这个药物。研究数据近期在瑞典斯德哥尔摩举办的第18届欧洲血液病协会(EHA)年会上公布。
研究者在去年12月美国血液病协会大会上也报告了一部分MCL和DLBCL患者的研究数据,而今年EHA会议上呈现的结果是对原有数据的进一步扩充。Ibrutinib治疗复发/难治性MCL患者的关键结果如下:
总体缓解率(ORR)为68%,其中21%为完全缓解(CR),即所有肿瘤征象均消失;47%为部分缓解(PR)。
所有获得缓解的患者中,中位缓解期(DOR)的估计值为17.5个月;中位无进展生存(PFS)为13.9个月;中位总生存(OS)尚未到达,但估计58%在18个月。
20%以上的患者报告了治疗期间的紧急不良事件(AEs),包括腹泻(50%),虚弱(41%),恶心(31%),周围性水肿(28%),呼吸困难(27%),便秘(25%),上呼吸道感染(23%),呕吐(23%)和食欲减退(21%),这些反应与上次报道的数据相同。仅8例患者因不良事件终止治疗。
英国普利茅斯Derriford医院血液病科的顾问血液病学家Simon Rule教授在EHA大会上展示了该研究的结果,他表示,MCL患者在接受单药治疗的情况下能取得这样的成果意义非凡,并意味着这种疗法前景广阔。而缓解率随时间的推移仍在继续增长,且没有新的安全警告出现,这样的事实格外使人欣慰。
另一项研究针对复发/难治性DLBCL患者,研究者评价了ibrutinib用于DLBCL的活化B细胞样(ABC)亚型是否比用于生发中心B细胞样(GCB)亚型更有效。DLBCL的ABC亚型依赖于B细胞抗原受体(BCR)通路,而BTK是其中的关键元素。
Ibrutinib能选择性抑制BTK,从而抑制恶性B细胞的生长和增殖。该项研究的主要结果如下:
1.单药治疗时,ABC亚型的患者与GCB亚型的患者相比,显示了对ibrutinib优先响应(ORR分别为41%和5%,Fisher精确检验)
2.ABC亚型和GCB亚型患者的中位OS分别为9.7个月和3.35个月。
3.70例患者的安全性数据未显示新的安全警告。3%以上的患者出现了3级以上的AEs,包括虚弱(9%),低钠血症(9%),肺炎(7%),脱水(4%)和胸膜渗出(4%)。
美国洛杉矶UCLA医学中心内科副教授Even de Vos作为研究者在EHA大会上汇报这些结果时表示,这些结果显示ibrutinib单药治疗对一部分参与实验的ABC亚型的DLBCL患者有效。由于ABC亚型的DLBCL患者难以治疗,这些结果展示了良好的前景。
-------------------------------------------------
注:以下产品不同规格和不同价格,购买以咨询为准!
-------------------------------------------------
产地国家: 美国
原产地英文商品名:
IMBRUVICA 140mgX90capsules
原产地英文药品名:
ibrutinib
中文参考商品译名:
IMBRUVICA 140毫克x90胶囊/瓶
中文参考药品译名:
依鲁替尼
生产厂家中文参考译名:
Pharmacyclics/Janssen Biotech Inc.
生产厂家英文名:
Pharmacyclics/Janssen Biotech Inc.
-----------------------------------------------------    
产地国家: 美国
原产地英文商品名:
IMBRUVICA 140mgX120capsules
原产地英文药品名:
ibrutinib
中文参考商品译名:
IMBRUVICA 140毫克x120胶囊/瓶
中文参考药品译名:
依鲁替尼
生产厂家中文参考译名:
Pharmacyclics/Janssen Biotech Inc.
生产厂家英文名:
Pharmacyclics/Janssen Biotech Inc.

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