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依鲁替尼硬胶囊|Imbruvica(ibrutinib hard capsules)

2015-07-26 00:47:50  作者:新特药房  来源:互联网  浏览次数:361  文字大小:【】【】【
简介:英文药名:Imbruvica(ibrutinib hard capsules) 中文药名:依鲁替尼硬胶囊(拉铁尼伯) 生产厂家:Pharmacyclics/Johnson&Johnson药品介绍2014年10月22日,抗癌药Imbruvica(ibrutinib)获欧盟委员 ...

英文药名:Imbruvica(ibrutinib hard capsules)

中文药名:依鲁替尼硬胶囊(拉铁尼伯)

生产厂家:Pharmacyclics/Johnson&Johnson
药品介绍
2014年10月22日,抗癌药Imbruvica(ibrutinib)获欧盟委员会(EC)批准,用于2种血液癌症:(1)用于复发性或难治性套细胞淋巴瘤(MCL)成人患者的治疗;(2)用于既往接受过至少一种疗法的慢性淋巴细胞白血病(CLL)成人患者的治疗;(3)用于携带del 17p删除突变或TP53突变且不适合化疗-免疫疗法的慢性淋巴细胞白血病(CLL)成人患者的一线治疗。
Imbruvica的获批,是基于在CLL患者中开展的III期RESONATE(PCYC-1112-CA)研究和Ib/II期研究(PCYC-1102)以及在MCL患者中开展的II期研究(PCYC-1104)的积极数据。
套细胞淋巴瘤(MCL)是一种罕见侵袭性B细胞淋巴瘤,该病难以治疗且预后很差。慢性淋巴细胞白血病(CLL)是一种源于骨髓白血细胞(淋巴细胞)的血癌。染色体异常删除突变del 17p和TP53突变与癌症的恶化和耐药性相关,del 17p删除突变是指17号染色体部分片段丢失,携带该突变的CLL患者被认为预后最差。
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需要的布鲁顿酪氨酸激酶(BTK)而起到抗癌的作用。BTK是B细胞受体信号复合体中的一种关键信号分子,在恶性B细胞的生存及扩散中起着重要作用。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。
FDA分别于2013年12月、2014年2月和2014年7月批准Imbruvica用于经治套细胞淋巴瘤(MCL)、经治慢性淋巴细胞白血病(CLL)、携带del 17p删除突变的CLL的治疗。强生旗下杨森生物科技与Pharmacyclics于2011年12月签署授权协议,联合开发Imbruvica以及该药在美国的商业化,强生拥有Imbruvica在整个EMEA(欧洲、中东和非洲)以及美国以外世界其他地区的商业化权利。
适应证和用途
IMBRUVICA是一个激酶抑制剂适用为患者的治疗:
⑴曾接受至少1次既往治疗有套细胞淋巴瘤(MCL)患者套细胞淋巴瘤(MCL) .
根据总体反应率对这个适应证授权加速批准。尚未确定生存或疾病相关症状的改进。继续批准这个适应证可能取决于在验证性试验中临床获益的确证。
⑵曾接受至少1次既往治疗的慢性淋巴细胞性白血病(CLL).
⑶慢性淋巴性白血病有 17p缺失。
剂量和给药方法
MCL: 560 mg口服每天1次(4粒140 mg胶囊每天1次)
CLL: 420 mg口服每天1次(3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
包装规格[本品德国上市包装]
140mgx90粒
140mgx120粒


Imbruvica 140 mg hard capsules
1. Name of the medicinal product
IMBRUVICA 140 mg hard capsules.
2. Qualitative and quantitative composition
Each hard capsule contains 140 mg of ibrutinib.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard capsule (capsule).
White opaque, hard capsule of 22 mm in length, marked with “ibr 140 mg” in black ink.
4. Clinical particulars
4.1 Therapeutic indications
IMBRUVICA is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.
IMBRUVICA is indicated for the treatment of adult patients with Waldenström's macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.
4.2 Posology and method of administration
Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Posology
Mantle cell lymphoma
The recommended dose for the treatment of MCL is 560 mg (four capsules) once daily.
Chronic lymphocytic leukaemia and Waldenström's macroglobulinaemia (WM)
The recommended dose for the treatment of CLL and WM is 420 mg (three capsules) once daily.
Treatment should continue until disease progression or no longer tolerated by the patient.
Dose adjustments
Moderate and strong CYP3A4 inhibitors increase the exposure of ibrutinib (see sections 4.4 and 4.5).
The IMBRUVICA dose should be lowered to 140 mg once daily (one capsule) when used concomitantly with moderate CYP3A4 inhibitors.
The IMBRUVICA dose should be reduced to 140 mg once daily (one capsule) or withheld for up to 7 days when it is used concomitantly with strong CYP3A4 inhibitors.
IMBRUVICA therapy should be withheld for any new onset or worsening grade ≥ 3 non-haematological toxicity, grade 3 or greater neutropenia with infection or fever, or grade 4 haematological 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, the once daily dose should be reduced by one capsule (140 mg). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue the medicinal product.
Recommended dose modifications are described below:

Toxicity occurrence

MCL dose modification after recovery

CLL/WM dose modification after recovery

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

Missed dose
If a dose 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. The patient should not take extra capsules to make up the missed dose.
Special populations
Elderly
No specific dose adjustment is required for elderly patients (aged ≥ 65 years).
Renal impairment
No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in IMBRUVICA clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained and serum creatinine levels monitored periodically. Administer IMBRUVICA to patients with severe renal impairment (< 30 mL/min creatinine clearance) only if the benefit outweighs the risk and monitor patients closely for signs of toxicity. There are no data in patients with severe renal impairment or patients on dialysis (see section 5.2).
Hepatic impairment
Ibrutinib is metabolised in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure (see section 5.2). For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 280 mg daily (two capsules). For patients with moderate liver impairment (Child-Pugh class B), the recommended dose is 140 mg daily (one capsule). Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with severe hepatic impairment (Child-Pugh class C).
Severe cardiac disease
Patients with severe cardiovascular disease were excluded from IMBRUVICA clinical studies.
Paediatric population
The safety and efficacy of IMBRUVICA in children aged 0 to 18 years have not been established. No data are available.
Method of administration
IMBRUVICA should be administered orally once daily with a glass of water approximately at the same time each day. The capsules should be swallowed whole with water and should not be opened, broken, or chewed. IMBRUVICA must not be taken with grapefruit juice or Seville oranges (see section 4.5).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use of preparations containing St. John's Wort is contraindicated in patients treated with IMBRUVICA.
4.4 Special warnings and precautions for use
Bleeding-related events
There have been reports of haemorrhagic events in patients treated with IMBRUVICA, both with and without thrombocytopenia. These include minor haemorrhagic events such as contusion, epistaxis, and petechiae; and major haemorrhagic events including gastrointestinal bleeding, intracranial haemorrhage, and haematuria.
Patients were excluded from participation in IMBRUVICA phase 2 and 3 studies if they required warfarin or other vitamin K antagonists. Warfarin or other vitamin K antagonists should not be administered concomitantly with IMBRUVICA. Supplements such as fish oil and vitamin E preparations should be avoided. Use of IMBRUVICA in patients requiring other anticoagulants or medicinal products that inhibit platelet function may increase the risk of bleeding, and particular care should be taken if anticoagulant therapy is used. Patients with congenital bleeding diathesis have not been studied.
IMBRUVICA should be held at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Leukostasis
Cases of leukostasis have been reported in patients treated with IMBRUVICA. A high number of circulating lymphocytes (> 400,000/mcL) may confer increased risk. Consider temporarily holding IMBRUVICA. Patients should be closely monitored. Administer supportive care including hydration and/or cytoreduction as indicated.
Infections
Infections (including sepsis, neutropenic sepsis, bacterial, viral, or fungal infections) were observed in patients treated with IMBRUVICA. Some of these infections have been associated with hospitalisation and death. Most patients with fatal infections also had neutropenia. Patients should be monitored for fever, neutropenia and infections and appropriate anti-infective therapy should be instituted as indicated.
Cytopenias
Treatment-emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anaemia) were reported in patients treated with IMBRUVICA. Monitor complete blood counts monthly.
Atrial fibrillation/flutter
Atrial fibrillation and atrial flutter have been reported in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor all patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms or new onset of dyspnoea should be evaluated clinically and if indicated have an electrocardiogram (ECG) performed.
In patients with preexisting atrial fibrillation requiring anticoagulant therapy, alternative treatment options to IMBRUVICA should be considered. In patients who develop atrial fibrillation on therapy with IMBRUVICA a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk and where alternatives to IMBRUVICA are non-suitable, tightly controlled treatment with anticoagulants should be considered.
Tumour lysis syndrome
Tumour lysis syndrome has been reported with IMBRUVICA therapy. Patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. Monitor patients closely and take appropriate precautions.
Effects on the QT interval
In a phase 2 study, ECG evaluations showed IMBRUVICA produced a mild decrease in QTcF interval (mean 7.5 ms). Although the underlying mechanism and safety relevance of this finding are not known, clinicians should use clinical judgment when assessing whether to prescribe ibrutinib to patients at risk from further shortening their QTc duration (e.g., Congenital Short QT Syndrome or patients with a family history of such a syndrome).
Drug-drug interactions
Co-administration of strong or moderate CYP3A4 inhibitors with IMBRUVICA may lead to increased ibrutinib exposure and consequently a higher risk for toxicity. On the contrary, co-administration of CYP3A4 inducers may lead to decreased IMBRUVICA exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of IMBRUVICA with strong or moderate CYP3A4 inhibitors/inducers should be avoided whenever possible and co-administration should only be considered when the potential benefits clearly outweigh the potential risks. Patients should be closely monitored for signs of IMBRUVICA toxicity if a CYP3A4 inhibitor must be used (see sections 4.2 and 4.5). If a CYP3A4 inducer must be used, closely monitor patients for signs of IMBRUVICA lack of efficacy.
Women of childbearing potential
Women of childbearing potential must use a highly effective method of contraception while taking IMBRUVICA (see section 4.6).
4.5 Interaction with other medicinal products and other forms of interaction
Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4.
Agents that may increase ibrutinib plasma concentrations
Concomitant use of IMBRUVICA and medicinal products that strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure and should be avoided.
Strong CYP3A4 inhibitors
Co-administration of ketoconazole, a strong CYP3A4 inhibitor, in 18 fasted healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by 29- and 24-fold, respectively. Simulations using fasted conditions suggested that the strong CYP3A4 inhibitor clarithromycin may increase the AUC of ibrutinib by a factor of 14. Strong inhibitors of CYP3A4 (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodon and cobicistat) should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the IMBRUVICA dose to 140 mg (one capsule) or withhold treatment temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).
Moderate CYP3A4 inhibitors
Simulations using fasted conditions suggested that moderate CYP3A4 inhibitors, diltiazem, erythromycin and voriconazole, may increase the AUC of ibrutinib 5-9 fold. Moderate inhibitors (e.g., voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) should be avoided. If a moderate CYP3A4 inhibitor must be used, reduce IMBRUVICA treatment to 140 mg (one capsule) for the duration of the inhibitor use. Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).
Mild CYP3A4 inhibitors
Simulations using clinically relevant fasted conditions suggested that the mild CYP3A4 inhibitors azithromycin and fluvoxamine may increase the AUC of ibrutinib by < 2-fold. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed.
Co-administration of grapefruit juice, containing CYP3A4 inhibitors, in eight healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by approximately 4- and 2-fold, respectively. Grapefruit and Seville oranges should be avoided during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A4 (see section 4.2).
Agents that may decrease ibrutinib plasma concentrations
Administration of IMBRUVICA with inducers of CYP3A4 can decrease ibrutinib plasma concentrations.
Co-administration of rifampicin, a strong CYP3A4 inducer, in 18 fasted healthy subjects, decreased exposure (Cmax and AUC) of ibrutinib by 92 and 90%, respectively. Avoid concomitant use of strong or moderate CYP3A4 inducers (e.g., carbamazepine, rifampicin, phenytoin). Preparations containing St. John's Wort are contraindicated during treatment with IMBRUVICA, as efficacy may be reduced. Consider alternative agents with less CYP3A4 induction. If the benefit outweighs the risk and a strong or moderate CYP3A4 inducer must be used, monitor patient closely for lack of efficacy (see sections 4.3 and 4.4). Mild inducers may be used concomitantly with IMBRUVICA, however, patients should be monitored for potential lack of efficacy.
As ibrutinib solubility is pH dependent, there is a theoretical risk that medicinal products increasing stomach pH (e.g., proton pump inhibitors) may decrease ibrutinib exposure. This interaction has not been studied in vivo.
Agents that may have their plasma concentrations altered by ibrutinib
Ibrutinib is a P-gp inhibitor in vitro. As no clinical data are available on this interaction, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic dose. To avoid a potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin should be taken at least 6 hours before or after IMBRUVICA.
There is a risk that ibrutinib may inhibit intestinal CYP3A4 and thereby increasing the exposure of CYP3A4 substrates with a large contribution of intestinal CYP3A4 metabolism to its first pass extraction. This interaction has not been studied in vivo and its clinical relevance is currently unknown.
4.6 Fertility, pregnancy and lactation
Women of child-bearing potential/Contraception in females
Based on findings in animals, IMBRUVICA may cause foetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking IMBRUVICA and for up to 3 months after ending treatment. Therefore, women of child-bearing potential must use highly effective contraceptive measures while taking IMBRUVICA and for three months after stopping treatment. It is currently unknown whether ibrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method.
Pregnancy
IMBRUVICA should not be used during pregnancy. There are no data from the use of IMBRUVICA in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Breast-feeding
It is not known whether ibrutinib or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with IMBRUVICA.
Fertility
No male or female fertility studies have been conducted (see section 5.3).
4.7 Effects on ability to drive and use machines
Fatigue, dizziness and asthenia have been reported in some patients taking IMBRUVICA and should be considered when assessing a patient's ability to drive or operate machines.
4.8 Undesirable effects
Summary of the safety profile
The safety profile is based on pooled data from 420 patients treated with IMBRUVICA in three phase 2 clinical studies and one randomised phase 3 study. Patients treated for MCL received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM received IMBRUVICA at 420 mg once daily. All patients received IMBRUVICA until disease progression or no longer tolerated.
The most commonly occurring adverse drug reactions (≥ 20%) were neutropenia, anaemia, diarrhoea, musculoskeletal pain, upper respiratory tract infection, bruising, rash, nausea and pyrexia. The most common grade 3/4 adverse drug reactions (≥ 5%) were anaemia, neutropenia, pneumonia and thrombocytopenia.
Tabulated list of adverse drug reactions
Treatment-emergent adverse drug reactions for MCL, CLL or WM are listed below by system organ class and frequency grouping. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1 Treatment-emergent adverse drug reactions (ADR) in patients treated with ibrutinib for MCL, CLL or WM (N = 420)

System organ class

Frequency

(All grades)

Adverse drug reactions

Infections and infestations

Very common

Pneumonia*

Upper respiratory tract infection

Urinary tract infection

Sinusitis*

Skin infection*

Common

Sepsis*

Blood and lymphatic system disorders

Very common

Neutropenia

Thrombocytopenia

Anaemia

Common

Febrile neutropenia

Leukocytosis

Lymphocytosis

Uncommon

Leukostasis

Metabolism and nutrition disorders

Common

Dehydration

Hyperuricaemia

Uncommon

Tumour lysis syndrome

Nervous system disorders

Very common

Dizziness

Headache

Eye disorders

Common

Vision blurred

Cardiac disorders

Common

Atrial fibrillation

Vascular disorders

Very common

Haemorrhage*

Epistaxis

Bruising*

Petechiae

Common

Subdural haematoma

Gastrointestinal disorders

Very common

Diarrhoea

Vomiting

Stomatitis*

Nausea

Constipation

Common

Dry mouth

Skin and subcutaneous tissue disorders

Very common

Rash*

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Musculoskeletal pain*

General disorders and administration site conditions

Very common

Pyrexia

Oedema peripheral

* Includes multiple adverse drug reaction terms.

Discontinuation and dose reduction due to ADRs
Of the 420 patients treated with IMBRUVICA for CLL, MCL or WM 4% discontinued treatment primarily due to adverse drug reactions. These included infections and subdural haematoma. Adverse drug reactions leading to dose reduction occurred in approximately 7% of patients.
Elderly
Of the 420 patients treated with IMBRUVICA, 59% were above 65 years of age. Grade 3 or higher adverse drug reactions occurred more frequently among elderly patients treated with IMBRUVICA (53% of patients age ≥ 65 versus 42% of younger patients ). Grade 3 or higher adverse drug reactions occuring more frequently among elderly patients were pneumonia, atrial fibrillation and urinary tract infection.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
E-mail: medsafety@hpra.ie
4.9 Overdose
There are limited data on the effects of IMBRUVICA overdose. No maximum tolerated dose was reached in the phase 1 study in which patients received up to 12.5 mg/kg/day (1,400 mg). There is no specific antidote for IMBRUVICA. Patients who ingested more than the recommended dose should be closely monitored and given appropriate supportive treatment.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE27.
Mechanism of action
Ibrutinib is a potent, small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and CLL. BTK's pivotal role in signalling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion. Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
Lymphocytosis
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and an absolute count > 5,000/mcL), often associated with reduction of lymphadenopathy, has been observed in about three fourths of patients with CLL treated with IMBRUVICA. This effect has also been observed in about one third of patients with relapsed or refractory MCL treated with IMBRUVICA. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis typically occurs during the first few weeks of IMBRUVICA therapy (median time 1.1 weeks) and typically resolves within a median of 8.0 weeks in patients with MCL and 18.7 weeks in patients with CLL. A large increase in the number of circulating lymphocytes (e.g., > 400,000/mcL) has been observed in some patients.
Lymphocytosis was not observed in patients with WM treated with IMBRUVICA.
Clinical efficacy and safety
Mantle cell lymphoma
The safety and efficacy of IMBRUVICA in patients with relapsed or refractory MCL were evaluated in a single open-label, multi-center phase 2 study (PCYC-1104-CA), of 111 patients. The median age was 68 years (range: 40 to 84 years), 77% were male and 92% were Caucasian. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 3 or greater were excluded from the study. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range: 1 to 5 treatments), including 35% with prior high-dose chemotherapy, 43% with prior bortezomib, 24% with prior lenalidomide, and 11% with prior autologous or allogeneic stem cell transplant. At baseline, 39% of patients had bulky disease (≥ 5 cm), 49% had high-risk score by Simplified MCL International Prognostic Index (MIPI), and 72% had advanced disease (extranodal and/or bone marrow involvement) at screening.
IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumour 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 2.
Table 2: Overall response rate (ORR) and duration of response (DOR) in patients with relapsed or refractory MCL (Study PCYC-1104-CA)

Total

N = 111

ORR (%)

67.6

95% CI (%)

(58.0, 76.1)

CR (%)

20.7

PR (%)

46.8

Median DOR (CR+PR) (months)

17.5 (15.8, NR)

Median time to initial response, months (range)

1.9 (1.4-13.7)

Median time to CR, months (range)

5.5 (1.7-11.5)

CI = confidence interval; CR = complete response;

PR = partial response; NR = not reached

The efficacy data was further evaluated by an Independent Review Committee (IRC) demonstrating an ORR of 69%, with a 21% complete response (CR) rate and a 48% partial response (PR) rate. The IRC estimated median DOR was 19.6 months.
The overall response to IMBRUVICA was independent of prior treatment including bortezomib and lenalidomide or underlying risk/prognostic factors, bulky disease, gender or age.
Chronic lymphocytic leukaemia
The safety and efficacy of IMBRUVICA in patients with CLL were demonstrated in one uncontrolled study and one randomised, controlled study. The open-label, multi-center study (PCYC-1102-CA) included 51 patients with relapsed or refractory CLL, who received 420 mg once daily. IMBRUVICA was administered until disease progression or unacceptable toxicity. The median age was 68 years (range: 37 to 82 years), median time since diagnosis was 80 months, and median number of prior treatments was 4 (range: 1 to 12 treatments), including 92.2% with a prior nucleoside analog, 98.0% with prior rituximab, 86.3% with a prior alkylator, 39.2% with prior bendamustine and 19.6% with prior ofatumumab. At baseline, 39.2% of patients had Rai Stage IV, 45.1% had bulky disease (≥ 5 cm), 35.3% had deletion 17p and 31.4% had deletion 11q.
ORR was assessed according to the 2008 International Workshop on CLL (IWCLL) criteria by investigators and IRC. At a median duration follow up of 16.4 months, the ORR by IRC for the 51 relapsed or refractory patients was 64.7% (95% CI: 50.1%, 77.6%), all PRs. The ORR including PR with lymphocytosis was 70.6%. Median time to response was 1.9 months. The DOR ranged from 3.9 to 24.2+ months. The median DOR was not reached.
A randomised, multi-center, open-label phase 3 study of IMBRUVICA versus ofatumumab (PCYC-1112-CA) was conducted in patients with relapsed or refractory CLL. Patients (n = 391) were randomised 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or ofatumumab for up to 12 doses (300/2,000 mg). Fifty-seven patients randomised 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 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 tumour ≥5 cm. Thirty-two percent of patients had deletion 17p and 31% had 11q deletion.
Progression free survival (PFS) as assessed by an IRC according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression for patients in the IMBRUVICA arm. 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 PCYC-1112-CA are shown in Table 3.
Table 3: Efficacy results in patients with chronic lymphocytic leukaemia (Study PCYC-1112-CA)


Endpoint

IMBRUVICA

N = 195

Ofatumumab

N = 196

Median progression free survival

Not reached

8.1 months

HR = 0.215 [95% CI: 0.146; 0.317]

Overall survivala

HR = 0.434 [95% CI: 0.238; 0.789]b

HR = 0.387 [95% CI: 0.216; 0.695]c

Overall response rated, e (%)

42.6

4.1

Overall response rate including PR with lymphocytosisd (%)

62.6

4.1

a Median OS not reached for both arms. p < 0.005 for OS.

b Patients randomised to ofatumumab were censored when starting IMBRUVICA if applicable.

c Sensitivity analysis in which crossover patients from the ofatumumab arm were not censored at the date of first dose of IMBRUVICA.

d Per IRC. Repeat CT scans required to confirm response.

e All PRs achieved; p < 0.0001 for ORR.

The efficacy was similar across all of the subgroups examined, including in patients with and without deletion 17p, a pre-specified stratification factor (Table 4).
Table 4:Subgroup analysis of progression free survival (Study PCYC-1112-CA)

N

Hazard Ratio

95% CI

All subjects

391

0.210

(0.143, 0.308)

Del17P

     

Yes

127

0.247

(0.136, 0.450)

No

264

0.194

(0.117, 0.323)

Refractory disease to purine analog

     

Yes

175

0.178

(0.100, 0.320)

No

216

0.242

(0.145, 0.404)

Age

     

< 65

152

0.166

(0.088, 0.315)

≥ 65

239

0.243

(0.149, 0.395)

Number of prior lines

     

< 3

198

0.189

(0.100, 0.358)

≥ 3

193

0.212

(0.130, 0.344)

Bulky disease

     

< 5 cm

163

0.237

(0.127, 0.442)

≥ 5 cm

225

0.191

(0.117, 0.311)

Hazard ratio based on non-stratified analysis

The Kaplan-Meier curve for PFS is shown in Figure 1.
Figure 1: Kaplan-Meier curve of progression-free survival (ITT Population) in Study PCYC-1112- CA
Waldenström's macroglobulinaemia
The safety and efficacy of IMBRUVICA in WM (IgM-excreting lymphoplasmacytic lymphoma) 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, and 60% of patients were anemic (haemoglobin ≤ 11 g/dL).
IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The primary endpoint in this study was ORR per investigator assessment. The ORR and DOR were assessed using criteria adopted from the Third International Workshop of Waldenström's macroglobulinaemia. Responses to IMBRUVICA are shown in Table 5.
Table 5: Overall response rate (ORR) and duration of response (DOR) in patients with WM

Total (N = 63)

ORR (%)

87.3

95% CI (%)

(76.5, 94.4)

VGPR (%)

14.3

PR (%)

55.6

MR (%)

17.5

Median DOR months (range)

NR (0.03+, 18.8+)

CI = confidence interval; NR = not reached; MR = minor response; PR = partial response; VGPR = very good partial response; ORR = MR+PR+VGPR

The median time to response was 1.0 month (range: 0.7-13.4 months).
Efficacy results were also assessed by an Independent Review Committee (IRC) demonstrating an ORR of 83%, with a 11% VGPR rate and a 51% PR rate.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with IMBRUVICA in all subsets of the paediatric population in MCL, CLL and lymphoplasmacytic lymphoma (LPL) (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Ibrutinib is rapidly absorbed after oral administration with a median Tmax of 1 to 2 hours. Absolute bioavailability in fasted condition (n = 8) was 2.9% (90% CI = 2.1 – 3.9) and doubled when combined with a meal. Pharmacokinetics of ibrutinib does not significantly differ in patients with different B-cell malignancies. 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 of ibrutinib in fasted condition resulted in approximately 60% of exposure (AUClast) as compared to either 30 minutes before, 30 minutes after (fed condition) or 2 hours after a high fat breakfast.
Distribution
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1,000 ng/mL. The apparent volume of distribution at steady state (Vd, ss/F) was approximately 10,000 L.
Metabolism
Ibrutinib is metabolised primarily by, CYP3A4 to produce a dihydrodiol metabolite with an inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. Involvement of CYP2D6 in the metabolism of ibrutinib appears to be minimal.
Therefore, no precautions are necessary in patients with different CYP2D6 genotypes.
Elimination
Apparent clearance (CL/F) is approximately 1,000 L/h. The half-life of ibrutinib is 4 to 13 hours.
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 faeces and < 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in faeces and none in urine.
Special populations
Elderly
Population pharmacokinetics indicated that age does not significantly influence ibrutinib clearance from the circulation.
Paediatric population
No pharmacokinetic studies were performed with IMBRUVICA in patients under 18 years of age.
Gender
Population pharmacokinetics data indicated that gender does not significantly influence ibrutinib clearance from the circulation.
Race
There are insufficient data to evaluate the potential effect of race on ibrutinib pharmacokinetics.
Body weight
Population pharmacokinetics data indicated that body weight (range: 41-146 kg; mean [SD]: 83 [19 kg]) had a negligible effect on ibrutinib clearance.
Renal impairment
Ibrutinib has minimal renal clearance; urinary excretion of metabolites is < 10% of the dose. No specific studies have been conducted to date in subjects with impaired renal function. There are no data in patients with severe renal impairment or patients on dialysis (see section 4.2).
Hepatic impairment
Ibrutinib is metabolised in the liver. A hepatic impairment trial, was performed in non-cancer subjects administered a single dose of 140 mg of medicinal product under fasting conditions. The effect of impaired liver function varied substantially between individuals, but on average a 2.7-, 8.2-, and 9.8-fold increase in ibrutinib exposure (AUClast) was observed in subjects with mild (n = 6, Child-Pugh class A), moderate (n = 10, Child-Pugh class B) and severe (n = 8, Child-Pugh class C) hepatic impairment, respectively. The free fraction of ibrutinib also increased with degree of impairment, with 3.0, 3.8 and 4.8% in subjects with mild, moderate and severe liver impairment, respectively, compared to 3.3% in plasma from matched healthy controls within this study. The corresponding increase in unbound ibrutinib exposure (AUCunbound, last) is estimated to be 4.1-, 9.8-, and 13-fold in subjects with mild, moderate, and severe hepatic impairment, respectively (see section 4.2).
Co-administration with CYP substrates
In vitro studies indicated that ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, and CYP2D6. Both ibrutinib and the dihydrodiol metabolite are at most weak inducers of CYP450 isoenzymes in vitro. Therefore, it is unlikely that the medicinal product has any clinically relevant drug-drug interactions with medicinal products that may be metabolised by the CYP450 enzymes.
Co-administration with transport substrates/inhibitors
In vitro studies indicated that ibrutinib is not a substrate of P-gp, OATP1B1 and OATP1B3. Ibrutinib is an in vitro inhibitor of P-gp (see section 4.5).
5.3 Preclinical safety data
The following adverse effects were seen in studies of 13-weeks duration in rats and dogs. Ibrutinib was found to induce gastrointestinal effects (soft faeces/diarrhoea and/or inflammation) and lymphoid depletion in rats and dogs with a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day in both species. Based on mean exposure (AUC) at the 560 mg/day clinical dose, AUC ratios were 2.6 and 21 at the NOAEL in male and female rats, and 0.4 and 1.8 at the NOAEL in male and female dogs, respectively. Lowest Observed Effect Level (LOEL) (60 mg/kg/day) margins in the dog are 3.6-fold (males) and 2.3-fold (females). In rats, moderate pancreatic acinar cell atrophy (considered adverse) was observed at doses of ≥ 100 mg/kg in male rats (AUC exposure margin of 2.6-fold) and not observed in females at doses up to 300 mg/kg/day (AUC exposure margin of 21.3-fold). Mildly decreased trabecular and cortical bone was seen in female rats administered > 100 mg/kg/day (AUC exposure margin of 20.3-fold). All gastrointestinal, lymphoid and bone findings recovered following recovery periods of 6-13 weeks. Pancreatic findings partially recovered during comparable reversal periods.
Juvenile toxicity studies have not been conducted.
Carcinogenicity/genotoxicity
Carcinogenicity studies have not been conducted with ibrutinib.
Ibrutinib has no genotoxic properties when tested in bacteria, mammalian cells or in mice.
Reproductive toxicity
In pregnant rats, ibrutinib at a dose of 80 mg/kg/day was associated with increased post-implantation loss and increased visceral (heart and major vessels) malformations and skeletal variations with an exposure margin 14 times the AUC found in patients at a daily dose of 560 mg. At a dose of ≥ 40 mg/kg/day, ibrutinib was associated with decreased foetal weights (AUC ratio of ≥ 5.6 as compared to daily dose of 560 mg in patients). Consequently the foetal NOAEL was 10 mg/kg/day (approximately 1.3 times the AUC of ibrutinib at a dose of 560 mg daily) (see section 4.6).
Fertility
Fertility studies with ibrutinib have not been conducted.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule content
croscarmellose sodium
magnesium stearate
microcrystalline cellulose
sodium laurilsulfate
Capsule shell
gelatin
titanium dioxide (E171)
Printing ink
shellac
iron oxide black (E172)
propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
HDPE bottles with a child-resistant polypropylene closure.
Each carton contains one bottle of either 90 or 120 hard capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
8. Marketing authorisation number(s)
EU/1/14/945/001 (90 hard capsules)
EU/1/14/945/002 (120 hard capsules)
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 21 October 2014
10. Date of revision of the text
3 July 2015
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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