|
——突破性抗癌药Imbruvica第4个适应症获欧盟批准
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, some fatal, 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. Interstitial Lung Disease (ILD) Cases of ILD have been reported in patients treated with IMBRUVICA. Monitor patients for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt IMBRUVICA and manage ILD appropriately. If symptoms persist, consider the risks and benefits of IMBRUVICA treatment and follow the dose modification guidelines. 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. Non-melanoma skin cancer Non-melanoma skin cancers were reported more frequently in patients treated with IMBRUVICA than in patients treated with comparators in pooled comparative randomised phase 3 studies. Monitor patients for the appearance of non-melanoma skin cancer. 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 (CYP3A4). 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 and breast cancer resistance protein (BCRP) inhibitor in vitro. As no clinical data are available on this interaction, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a therapeutic dose. To minimise the potential for an interaction in the GI tract, oral narrow therapeutic range, P-gp or BCRP substrates such as digoxin or methotrexate should be taken at least 6 hours before or after IMBRUVICA. Ibrutinib may also inhibit BCRP in the liver and increase the exposure of drugs that undergo BCRP-mediated hepatic efflux, such as rosuvastatin. Based on in vitro data, ibrutinib is a weak reversible inhibitor towards CYP3A4 at the intestinal level and may therefore increase the exposure to CYP3A4 substrates sensitive to gut CYP3A metabolism. No clinical data are available on this interaction. Caution should be exercised if co-administering ibrutinib with CYP3A4 substrates administered orally with narrow therapeutic range (such as dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus and tacrolimus). Based on in vitro data, ibrutinib is a weak CYP2B6 inducer and may have the potential to affect the expression of other enzymes and transporters regulated via the constitutive androstane receptor (CAR), e.g. CYP2C9, CYP2C19, UGT1A1 and MRP2. The clinical relevance is not known, but the exposure to substrates of CYP2B6 (such as efavirenz and bupropion) and of co-regulated enzymes may be reduced upon co-administration with ibrutinib. 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 effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED]16 mg/kg/day) (see section 5.3). No human data on the effects of ibrutinib on fertility are available. 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 981 patients treated with IMBRUVICA in three phase 2 clinical studies and four randomised phase 3 studies and from post-marketing experience. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated. The most commonly occurring adverse reactions (≥ 20%) were diarrhoea, neutropenia, haemorrhage (e.g., bruising), musculoskeletal pain, nausea, rash, and pyrexia. The most common grade 3/4 adverse reactions (≥ 5%) were neutropenia, pneumonia, thrombocytopenia, and febrile neutropenia. Tabulated list of adverse reactions Adverse reactions in patients treated with ibrutinib for B-cell malignancies and post-marketing adverse reactions 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1: Adverse drug reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignancies†
Includes multiple adverse reaction terms. Includes events with fatal outcome. a Spontaneous reports from post-marketing experience. Discontinuation and dose reduction due to adverse drug reactions Of the 981 patients treated with IMBRUVICA for B-cell malignancies, 5% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation and haemorrhage. Adverse reactions leading to dose reduction occurred in approximately 5% of patients. Elderly Of the 981 patients treated with IMBRUVICA, 62% were 65 years of age or older. Grade 3 or higher pneumonia occurred more frequently among elderly patients treated with IMBRUVICA (13% of patients age ≥ 65 versus 7% of patients < 65 years of age). 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/day). In a separate study, one healthy subject who received a dose of 1,680 mg experienced reversible grade 4 hepatic enzyme increases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)]. 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 month of IMBRUVICA therapy and typically resolves within a median of 8.0 weeks in patients with MCL and 14 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)
The overall response to IMBRUVICA was independent of prior treatment including bortezomib and lenalidomide or underlying risk/prognostic factors, bulky disease, gender or age. The safety and efficacy of IMBRUVICA were demonstrated in a randomised phase 3, open-label, multicenter study including 280 patients with MCL who received at least one prior therapy (Study MCL3001). Patients were randomised 1:1 to receive either IMBRUVICA orally at 560 mg once daily for 21 days or temsirolimus intravenously at 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Treatment on both arms continued until disease progression or unacceptable toxicity. The median age was 68 years (range, 34; 88), 74% were male and 87% were Caucasian. The median time since diagnosis was 43 months, and median number of prior treatments was 2 (range: 1 to 9 treatments), including 51% with prior high-dose chemotherapy, 18% with prior bortezomib, 5% with prior lenalidomide, and 24% with prior stem cell transplant. At baseline, 53% of patients had bulky disease (≥ 5 cm), 21% had high-risk score by Simplified MIPI, 60% had extranodal disease and 54% had bone marrow involvement at screening. Progression-free survival (PFS) was assessed by IRC according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. Efficacy results for Study MCL3001 are shown in Table 3 and the Kaplan-Meier curve for PFS in Figure 1. Table 3: Efficacy Results in patients with relapsed or refractory MCL (Study MCL3001)
Figure 1: Kaplan-Meier curve of progression-free survival (ITT Population) in Study MCL3001
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 6). Table 6: Subgroup analysis of progression free survival (Study PCYC-1112-CA)
The Kaplan-Meier curve for PFS is shown in Figure 4. Figure 4: Kaplan-Meier curve of progression-free survival (ITT Population) in Study PCYC-1112- CA
b Median OS not reached for both arms 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 or 6.8 mmol/L). 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 8. Table 8: Overall response rate (ORR) and duration of response (DOR) in patients with WM
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 reversible inhibitor toward CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and intestinal (but not hepatic) CYP3A4 and does not display clinically relevant time-dependent inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6. The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, and CYP2D6. The dihydrodiol metabolite is at most a weak inducer of CYP450 isoenzymes in vitro. Although ibrutinib is a sensitive CYP3A4 substrate, it does not have a clinically relevant effect on its own exposure. Co-administration with transport substrates/inhibitors In vitro studies indicated that ibrutinib is not a substrate of P-gp, nor other major transporters, except OCT2. The dihydrodiol metabolite and other metabolites are P-gp substrates. Ibrutinib is an in vitro inhibitor of P-gp and BCRP (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). In pregnant rabbits, ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal malformations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased post-implantation loss. Ibrutinib caused malformations in rabbits at a dose of 15 mg/kg/day (approximately 2.0 times the exposure (AUC) in patients with MCL administered ibrutinib 560 mg daily and 2.8 times the exposure in patients with CLL or WM receiving ibrutinib dose 420 mg per day). Consequently the foetal NOAEL was 5 mg/kg/day (approximately 0.7 times the AUC of ibrutinib at a dose of 560 mg daily) (see section 4.6). Fertility No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED]16 mg/kg/day). 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 25 August 2016 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 欧洲批准IMBRUVICA(ibrutinib)用于巨球蛋白血症的治疗 AbbVie宣布欧盟委员会（EC）对IMBRUVICA（ibrutinib）发放上市许可。IMBRUVICA（ibrutinib）现已成为欧盟所有28个国家中针对Waldenstrom巨球蛋白血症的第一个可用治疗药物。Waldenstrom巨球蛋白血症（WM）是一种在至少接受过一次先前治疗的成年病人或接受一线治疗并且不适合化学免疫治疗的病人中发现的罕见的、生长缓慢的血液癌症。AbbVie旗下Pharmacyclics有限责任公司已经收到了FDA对于IMBRUVICA的批准，IMBRUVICA是在美国的第一个，也是唯一一个FDA批准的针对Waldenstrom巨球蛋白血症的治疗药物。由于获得IMBRUVICA用于治疗Waldenstrom巨球蛋白血症的批准，Janssen公司因此启动了2000万$的资金。 IMBRUVICA是由Pharmacyclics和Janssen Biotech公司在美国合作开发并运营，在欧洲市场及世界其他市场上，Janssen-Cilag international NV持有其上市许可。在欧洲，IMBRUVICA已经被批准用于治疗患有复发或难治性套细胞淋巴瘤（MCL）和已经接受过至少一次先前治疗或接受一线治疗且因为17p缺失或因存在TP53变异而不适合化学免疫疗法的慢性淋巴细胞白血病（CLL）的成年患者。 Pharmacyclics主席Wulff-Erik von Borcke 表示，“IMBRUVICA作为第一个也是唯一一个由欧盟委员会批准用于治疗Waldenstrom巨球蛋白血症的药物，其对于需要医疗援助的病患的价值不言而喻。”“同时，我们很高兴IMBRUVICA已经可以对在欧洲的Waldenstrom巨球蛋白血症患者提供帮助了。” 欧盟委员会的审批是基于一项二阶多中心研究展开的。这项研究会评估63位接受了两个先前疗法（范围1-9）的患有Waldenstrom巨球蛋白血症的患者在每天接受420mgIMBRUVICA治疗时其有效性和耐受性。这项研究的最新的结果已经在新英格兰医学杂志上发表，其结果表明在最多19个月（0.5-29.7）的中位随访中IMBRUVICA与91%的总反应率（ORR；主要终点）相关，调查员采用了Waldenstrom巨球蛋白血症国际研讨会的标准进行本次调查。调查结果为11位病人（17%）有轻微反应（MR），36位病人（57%）有部分反（PR），10位病人（16%）有极佳部分反应，随访结果表明，达到轻微反应和部分反应分别需要4周和8周治疗。 次要终点包括无进展生存率（PFS）和安全性。24个月的预估无进展生存率和总生存率（OS）分别是69%(95% CI, 53.2 - 80.5)和95%(95% CI, 86.0 to 98.4)。IMBRUVICA最常见的不良反应（>20%）包括白细胞减少、血小板减少症、腹泻、皮疹、恶心、肌肉痉挛和疲劳。有6%接受IMBRUVICA治疗的患者因不良反应而中断治疗。总体而言，IMBRUVICA拥有良好耐受性且安全性与先前的观察保持一致。 关于Waldenstrom巨球蛋白血症 Waldenstrom巨球蛋白血症（临床公认的亚型淋巴浆细胞淋巴瘤或LPL）是一种生长缓慢且罕见的血液癌症，最常见的起源为位于骨髓中的淋巴B细胞。Waldenstrom巨球蛋白血症由淋巴B细胞在健康的生命周期中发生功能障碍导致，此时该细胞表现出癌症症状并以异常的速率开始分裂。癌变的B细胞产生大量的免疫球蛋白M（lgM抗体），大量的lgM导致血液变的粘稠从而引起其他的Waldenstrom巨球蛋白血症症状。 关于IMBRUVICA IMBRUVICA是目前在美国批准的用于针对至少接受了一次先前治疗的患者治疗慢性淋巴细胞白血病（CLL）、所有有del17P（一种因17号染色体丢失导致的基因变异）的慢性淋巴细胞白血病患者（包括从未进行治疗的患者）和所有Waldenstrom巨球蛋白血症的患者（包括初治患者）进行治疗的药物。同时IMBRUVICA也获得批准用于针对接受过至少一次先前治疗的患者治疗套细胞淋巴瘤（MCL）。 IMBRUVICA（ibrutinib）是一种新型药物，用法为口服，每日一次。其作用为抑制一种叫做布鲁顿酪氨酸激酶(BTK)的蛋白质。IMBRUVICA是第一批通过突破性治疗指定通道获得美国FDA批准的药物之一，也是唯一一个获得三次突破性治疗认定资格的药物。 布鲁顿酪氨酸激酶（BTK）是B细胞受体信号传导复合体中的关键分子，受体信号传导复合体是癌变B细胞生存和传播的重要细胞器。IMBRUVICA通过抑制BTK阻止了癌变B细胞的不受控传播和分裂信号的传播。 IMBRUVICA已经被单独用于或结合其他治疗方法治疗多种血癌的临床试验中。已有超过800名研究人员针对超过6100名患者在35个不同的国家进行的临床试验中使用了IMBRUVICA。 ------------------------------------------------- 产地国家: 德国 原产地英文商品名: IMBRUVICA hard capsules 140mg/capsules 90capsules 原产地英文药品名: ibrutinib 中文参考商品译名: IMBRUVICA 140毫克 90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: 德国 原产地英文商品名: IMBRUVICA hard capsules 140mg/capsules 120capsules 原产地英文药品名: ibrutinib 中文参考商品译名: IMBRUVICA 140毫克 120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: 瑞士 原产地英文商品名: IMBRUVICA Kaps 140mg/capsules 90capsules 原产地英文药品名: ibrutinib 中文参考商品译名: IMBRUVICA 140毫克 90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: Janssen-Cilag AG 生产厂家英文名: Janssen-Cilag AG ------------------------------------------------- 产地国家: 瑞士 原产地英文商品名: IMBRUVICA Kaps 140mg/capsules 120capsules 原产地英文药品名: ibrutinib 中文参考商品译名: IMBRUVICA 140毫克 120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: Janssen-Cilag AG 生产厂家英文名: Janssen-Cilag AG | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
