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美国FDA批准淋巴瘤治疗新药IMBRUVICA (ibrutinib)上市

2014-01-11 22:30:02  作者:新特药房  来源:互联网  浏览次数:1036  文字大小:【】【】【
简介: IMBRUVICA (ibrutinib) capsule[Pharmacyclics, Inc]当地时间2013年11月13日,Ibrutinib的先期开发者Pharmacyclics公司在其网站主页宣布,美国食品药品管理局(USFDA)已批准Ibrutinib(商标名 IMBRUVI ...

IMBRUVICA (ibrutinib) capsule
[Pharmacyclics, Inc]
当地时间2013年11月13日,Ibrutinib的先期开发者Pharmacyclics公司在其网站主页宣布,美国食品药品管理局(USFDA)已批准Ibrutinib(商标名 IMBRUVICA)作为套细胞淋巴癌的单个治疗药物,适用于之前用其他手段治疗过的套细胞淋巴癌患者,标志着该药物正式进入市场化运营阶段。
Ibrutinib早先由Pharmacyclics公司单独开发。2011年,强生(JNJ)旗下子公司杨森制药(Jassen)通过先期支付1.5亿美元而获得与Pharma -cyclics公司合作开发的权利。这款药物于今年2月份已被FDA授予突破性治疗药物资格。杨森制药于7月份向FDA提交了这款药物的上市申请,该药物用于治疗两种B细胞恶性肿瘤,即作为二线治疗药物用于慢性淋巴细胞性白血病(CLL)/小淋巴细胞淋巴瘤(SLL)和套细胞淋巴癌(MCL)治疗。10月份,杨森制药再次宣布,已向欧洲药品管理局(EMA)提交了抗癌药物Ibrutinib的上市许可申请(MAA),寻求批准用于上述三种血液性肿瘤的治疗。
此次Ibrutinib用于治疗套细胞淋巴癌获得批准是在对111名之前经历过治疗的患者进行全面试验的基础上做出的。药物效用结果显示,Ibrutinib在上述111名被试中的总体应答率高达65.8%,完全应答率达到17%,另有49%的患者为部分应答。持续应答时间的中值为17.5个月。
美国每年大约有1.6万人被诊断为慢性淋巴细胞性白血病,目前该疾病的标准治疗通常是化疗。然而,好多慢性淋巴细胞性白血病老年患者无法容忍激进的治疗,而染色体17p缺失引起的恶性肿瘤患者通常对治疗没有响应。在临床试验中,Ibrutinib已证实有较高的总体响应和持续响应,不论染色体17p状态如何。因此,Ibrutinib的批准将为相关的患者带来福音。
早先有分析师已预测Ibrutinib所有适应症的年销售峰值将会达到大约5亿美元,其最大销售份额可能来自慢性淋巴细胞性白血病适应症,而目前该适应症正在进行三项期临床试验。Ibrutinib在治疗套细胞淋巴癌领域的首先批准相信会让处于III临床试验的其他几种适应症被批准的希望大增。
关于Ibrutinib
Ibrutinib是一种名为Bruton’s酪氨酸激酶(BTK)抑制剂的首创新药。BTK是细胞生理活动中的一个重要蛋白,参与介导调控B细胞成熟和生存的胞内信号通路。在恶性B细胞中,B细胞受体信号通路过度活跃,该信号通路即包括BTK。Ibrutinib能够与BTK形成强有力的共价键,从而抑制恶性B细胞中过度活跃的细胞生存信号的传输,从而达到抑制肿瘤生长和转移的效果。
 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
强生(JNJ)和Pharmacyclics 11月13日宣布,FDA已批准血癌药物ibrutinib(拟用商品名为Imbruvica),用于既往已接受至少一种其他药物(如Celgene公司的Revlimid)治疗的套细胞淋巴瘤(mantle cell lymphoma,MCL)成人患者的治疗。该药成为获得FDA突破疗法认定并获批的第2个药物,ibrutinib将成为上市的首个BTK靶向药物。
FDA于本月早些时候批准了罗氏(Roche)的Gazyva,用于治疗慢性淋巴细胞白血病(CLL),是首个获FDA突破疗法认定并获批的药物。
在美国,套细胞淋巴瘤(MCL)占到了非霍奇金淋巴瘤病例的6%,该病在确诊时,通常已扩散至淋巴结、骨骼和其他器官。
目前,ibrutinib也正在等待FDA批准用于CLL。一些分析人士原以为,FDA会同时批准ibrutinib用于MCL和CLL。
RBC资本市场分析师Michael Yee预计,ibrutinib的长期年度全球销售额将达到50亿美元。
Ibrutinib由杨森与Pharmacyclics合作开发,目前正调查用于数种类型血癌的治疗。
强生分别于今年7月10日和10月30日向FDA和欧洲药品管理局(EMA)提交了Ibrutinib的上市许可申请(MAA),寻求批准用于复发性或难治性慢性淋巴细胞白血病(CLL)/小淋巴细胞白血病(SLL)或复发性或难治性套细胞淋巴瘤(MCL)成人患者的治疗。
CLL/SLL和MCL属于一组名为B细胞恶性肿瘤的血液癌症。许多患者在治疗后会复发,可能在治疗过程中使用数种药物。
关于Ibrutinib:
Ibrutinib是一种名为Bruton酪氨酸激酶(BTK)抑制剂的首创新药。BTK是一个重要的蛋白,参与介导调控B细胞成熟和生存的胞内信号通路。在恶性B细胞中,B细胞受体信号通路过度活跃,该信号通路即包括BTK。
Ibrutinib能够与BTK形成强有力的共价键,从而抑制恶性B细胞中过度活跃的细胞生存信号的传输。


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).
This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established (14.1).
DOSAGE AND ADMINISTRATION
560 mg taken orally once daily (four 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 (5.1).
Infections: Monitor patients for fever and infections and eva luate promptly. (5.2).
Myelosuppression: Check complete blood counts monthly (5.3).
Renal Toxicity: Monitor renal function and maintain hydration (5.4).
Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas (5.5).
Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to avoid pregnancy while taking the drug (5.6).
ADVERSE REACTIONS
The most common adverse reactions (≥20%) in patients with MCL 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 (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: Avoid use of IMBRUVICA in patients with baseline hepatic impairment (8.7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2013

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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)].

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 for Mantle Cell Lymphoma

The recommended dose of IMBRUVICA for MCL is 560 mg (four 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
First Restart at 560 mg daily
Second Restart at 420 mg daily
Third Restart at 280 mg daily
Fourth 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 had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily.

The mechanism for the bleeding events is not well understood.

Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding ibrutinib 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 (14.1)].

5.2 Infections

Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions (6)]. Monitor patients for fever and infections and eva luate promptly.

5.3 Myelosuppression

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). 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 and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically monitor creatinine levels. Maintain hydration.

5.5 Second Primary Malignancies

Other malignancies (5%) have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers (4%), and other carcinomas (1%).

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 receiving the ibrutinib dose of 560 mg per day. 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.

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 nutritional 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.

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 eva luated 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 administered the dose of 560 mg daily. 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.

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 observed in patients at 560 mg is (mean ± standard deviation) 953 ± 705 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 eva luated 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 3.

Table 3: 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 (median time 1.1 weeks) of IMBRUVICA therapy and resolves by a median of 8 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.

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