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英文药名：ENTYVIO(vedolizumab for solution for infusion) 中文药名：注射用维多珠单抗 生产厂家：德国Takeda药业
Infusion-related reactions In GEMINI I and II controlled studies, 4% of vedolizumab-treated patients and 3% of placebo-treated patients experienced an adverse event defined by the investigator as infusion-related reaction (IRR) (see section 4.4). No individual Preferred Term reported as an IRR occurred at a rate above 1%. The majority of IRRs were mild or moderate in intensity and <1% resulted in discontinuation of study treatment. Observed IRRs generally resolved with no or minimal intervention following the infusion. Most infusion related reactions occurred within the first 2 hours. Of those patients who had infusion related reactions, those dosed with vedolizumab had more infusion related reactions with in the first two hours as compared to placebo patients with infusion related reactions. Most infusion related reactions were not serious and occurred during the infusion or within the first hour after infusion is completed. One serious adverse event of IRR was reported in a Crohn's disease patient during the second infusion (symptoms reported were dyspnoea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) and was successfully managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In patients who received vedolizumab at Weeks 0 and 2 followed by placebo, no increase in the rate of IRR was seen upon retreatment with vedolizumab after loss of response. Infections In GEMINI I and II controlled studies, the rate of infections was 0.85 per patient-year in the vedolizumab-treated patients and 0.70 per patient-year in the placebo-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infections. Most patients continued on vedolizumab after the infection resolved. In GEMINI I and II controlled studies, the rate of serious infections was 0.07 per patient year in vedolizumab-treated patients and 0.06 per patient year in placebo-treated patients. Over time, there was no significant increase in the rate of serious infections. In controlled and open-label studies in adults with vedolizumab, serious infections have been reported, which include tuberculosis, sepsis (some fatal), salmonella sepsis, listeria meningitis, and cytomegaloviral colitis. Immunogenicity In GEMINI I and II controlled studies, vedolizumab showed an immunogenicity rate of 4% (56 of 1,434 patients who received continuous treatment with vedolizumab were anti-vedolizumab antibody-positive at any time during treatment). Nine out of 56 patients were persistently positive (anti-vedolizumab antibody-positive at two or more study visits) and 33 patients developed neutralizing anti-vedolizumab antibodies. The frequency of anti-vedolizumab antibody detected in patients 16 weeks after the last dose of vedolizumab (approximately five half-lives after the last dose) was approximately 10% in GEMINI I and II. In GEMINI I and II controlled studies, 5% (3 of 61) of the patients who had an adverse event assessed by the investigator as an IRR were persistently anti-vedolizumab antibody-positive. Overall, there was no apparent correlation of anti-vedolizumab antibody development to clinical response or adverse events. However, the number of patients that developed anti-vedolizumab antibodies was too limited to make a definitive assessment. Malignancy Overall, results from the clinical program to date do not suggest an increased risk for malignancy with vedolizumab treatment; however, the number of malignancies was small and long-term exposure was limited. Long-term safety evaluations are ongoing. 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Doses up to 10 mg/kg (approximately 2.5 times the recommended dose) have been administered in clinical trials. No dose-limiting toxicity was seen in clinical trials. 5. Pharmacological properties Pharmacotherapeutic group: immunosuppressants, selective immunosuppressants, ATC code: L04AA33 5.1 Pharmacodynamic properties Vedolizumab is a gut-selective immunosuppressive biologic. It is a humanized monoclonal antibody that binds specifically to the α4β7 integrin, which is preferentially expressed on gut homing T helper lymphocytes. By binding to α4β7 on certain lymphocytes, vedolizumab inhibits adhesion of these cells to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), but not to vascular cell adhesion molecule-1 (VCAM-1). MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to tissues within the gastrointestinal tract. Vedolizumab does not bind to, nor inhibit function of, the α4β1 and αEβ7 integrins. The α4β7 integrin is expressed on a discrete subset of memory T helper lymphocytes which preferentially migrate into the gastrointestinal (GI) tract and cause inflammation that is characteristic of ulcerative colitis and Crohn's disease, both of which are chronic inflammatory immunologically mediated conditions of the GI tract. Vedolizumab reduces gastrointestinal inflammation in UC patients. Inhibiting the interaction of α4β7 with MAdCAM-1 with vedolizumab prevents transmigration of gut-homing memory T helper lymphocytes across the vascular endothelium into parenchymal tissue in nonhuman primates and induced a reversible 3-fold elevation of these cells in peripheral blood. The murine precursor of vedolizumab alleviated gastrointestinal inflammation in colitic cotton-top tamarins, a model of ulcerative colitis. In healthy subjects, ulcerative colitis patients, or Crohn's disease patients, vedolizumab does not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T lymphocytes, total memory T helper lymphocytes, monocytes or natural killer cells, in the peripheral blood with no leukocytosis observed. Vedolizumab did not affect immune surveillance and inflammation of the central nervous system in Experimental Autoimmune Encephalomyelitis in non-human primates, a model of multiple sclerosis. Vedolizumab did not affect immune responses to antigenic challenge in the dermis and muscle (see section 4.4). In contrast, vedolizumab inhibited an immune response to a gastrointestinal antigenic challenge in healthy human volunteers (see section 4.4). Pharmacodynamic effects In clinical trials with vedolizumab at doses ranging from 2 to 10 mg/kg, >95% saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut immune surveillance was observed in patients. Vedolizumab did not affect CD4+ and CD8+ trafficking into the CNS as evidenced by the lack of change in the ratio of CD4+/CD8+ in cerebrospinal fluid pre- and post-vedolizumab administration in healthy human volunteers. These data are consistent with investigations in nonhuman primates which did not detect effects on immune surveillance of the CNS. Clinical efficacy Ulcerative Colitis The efficacy and safety of vedolizumab for the treatment of adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub score ≥2) was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at Week 6 and Week 52 (GEMINI I). Enrolled patients had failed at least one conventional therapy, including corticosteroids, immunomodulators, and/or the TNFα antagonist infliximab (including primary non-responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/or immunomodulators were permitted. For the evaluation of the Week 6 endpoints, 374 patients were randomised in a double-blind fashion (3:2) to receive vedolizumab 300 mg or placebo at Week 0 and Week 2. Primary endpoint was the proportion of patients with clinical response (defined as reduction in complete Mayo score of ≥3 points and ≥30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point) at Week 6. Table 2 shows the results from the primary and secondary endpoints evaluated.
In GEMINI I, two cohorts of patients received vedolizumab at Week 0 and Week 2: cohort 1 patients were randomised to receive either vedolizumab 300 mg or placebo in a double-blind fashion, and cohort 2 patients were treated with open-label vedolizumab 300 mg. To evaluate efficacy at Week 52, 373 patients from cohort 1 and 2 who were treated with vedolizumab and had achieved clinical response at Week 6 were randomised in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 300 mg every four weeks, or placebo every four weeks. Beginning at Week 6, patients who had achieved clinical response and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen. Primary endpoint was the proportion of patients in clinical remission at Week 52. Table 3 shows the results from the primary and secondary endpoints evaluated.
Patients who failed to demonstrate response at Week 6 remained in the study and received vedolizumab every four weeks. Clinical response using partial Mayo scores was achieved at Week 10 and Week 14 by greater proportions of vedolizumab patients (32% and 39%, respectively) compared with placebo patients (15% and 21%, respectively). Patients who lost response to vedolizumab when treated every eight weeks were allowed to enter an open-label extension study and receive vedolizumab every four weeks. In these patients, clinical remission was achieved in 25% of patients at Week 28 and Week 52. Patients who achieved a clinical response after receiving vedolizumab at Week 0 and 2 and were then randomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-label extension study and receive vedolizumab every four weeks. In these patients, clinical remission was achieved in 45% of patients by 28 weeks and 36% of patients by 52 weeks. In this open-label extension study, the benefits of vedolizumab treatment as assessed by partial Mayo score, clinical remission, and clinical response were shown for up to 124 weeks. Health-related quality of life (HRQOL) was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ), a disease specific instrument, and SF-36 and EQ-5D, which are general measures. Exploratory analysis show clinically meaningful improvements were observed for vedolizumab groups, and the improvements were significantly greater as compared with the placebo group at Week 6 and Week 52 on EQ-5D and EQ-5D VAS scores, all subscales of IBDQ (bowel symptoms, systemic function, emotional function and social function), and all subscales of SF-36 including the Physical Component Summary (PCS) and Mental Component Summary (MCS). Crohn's Disease The efficacy and safety of vedolizumab for the treatment of adult patients with moderately to severely active Crohn's Disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450) were evaluated in two studies (GEMINI II and III). Enrolled patients have failed at least one conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists (including primary non-responders). Concomitant stable doses of oral corticosteroids, immunomodulators, and antibiotics were permitted. The GEMINI II Study was a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at Week 6 and Week 52. Patients (n=368) were randomised in a double-blind fashion (3:2) to receive two doses of vedolizumab 300 mg or placebo at Week 0 and Week 2. The two primary endpoints were the proportion of patients in clinical remission (defined as CDAI score ≤150 points) at Week 6 and the proportion of patients with enhanced clinical response (defined as a ≥100-point decrease in CDAI score from baseline) at Week 6 (see Table 4). GEMINI II contained two cohorts of patients that received vedolizumab at Weeks 0 and 2: Cohort 1 patients were randomised to receive either vedolizumab 300 mg or placebo in a double-blind fashion, and Cohort 2 patients were treated with open-label vedolizumab 300 mg. To evaluate efficacy at Week 52, 461 patients from Cohorts 1 and 2, who were treated with vedolizumab and had achieved clinical response (defined as a ≥70-point decrease in CDAI score from baseline) at Week 6,were randomised in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 300 mg every four weeks, or placebo every four weeks. Patients showing clinical response at Week 6 were required to begin corticosteroid tapering. Primary endpoint was the proportion of patients in clinical remission at Week 52 (see Table 5). The GEMINI III Study was a second randomised, double-blind, placebo-controlled study that evaluated efficacy at Week 6 and Week 10 in the subgroup of patients defined as having failed at least one conventional therapy and failed TNFα antagonist therapy (including primary non-responders) as well as the overall population, which also included patients who failed at least one conventional therapy and were naïve to TNFα antagonist therapy. Patients (n=416), which included approximately 75% TNFα antagonist failures patients, were randomised in a double-blind fashion (1:1) to receive either vedolizumab 300 mg or placebo at Weeks 0, 2, and 6. The primary endpoint was the proportion of patients in clinical remission at Week 6 in the TNFα antagonist failure subpopulation. As noted in Table 4, although the primary endpoint was not met, exploratory analyses show that clinically meaningful results were observed.
Exploratory analyses provide additional data on key subpopulations studied. In GEMINI II, approximately half of patients had previously failed TNFα antagonist therapy. Among these patients, 28% receiving vedolizumab every eight weeks, 27% receiving vedolizumab every four weeks, and 13% receiving placebo achieved clinical remission at Week 52. Enhanced clinical response was achieved in 29%, 38%, 21%, respectively, and corticosteriod-free clinical remission was achieved in 24%, 16%, 0%, respectively. Patients who failed to demonstrate response at Week 6 in GEMINI II were retained in the study and received vedolizumab every four weeks. Enhanced clinical response was observed at Week 10 and Week 14 for greater proportions of vedolizumab patients 16% and 22%, respectively, compared with placebo patients 7% and 12%, respectively. There was no clinically meaningful difference in clinical remission between treatment groups at these time points. Analyses of Week 52 clinical remission in patients who were non-responders at Week 6 but achieved response at Week 10 or Week 14 indicate that non-responder CD patients may benefit from a dose of vedolizumab at Week 10. Patients who lost response to vedolizumab when treated every eight weeks in GEMINI II were allowed to enter an open-label extension study and received vedolizumab every four weeks. In these patients, clinical remission was achieved in 23% of patients at Week 28 and 32% of patients at Week 52. Patients who achieved a clinical response after receiving vedolizumab at Week 0 and 2 and were then randomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-label extension study and receive vedolizumab every four weeks. In these patients, clinical remission was achieved in 46% of patients by 28 weeks and 41% of patients by 52 weeks. In this open-label extension study, clinical remission and clinical response were observed in patients for up to 124 weeks. Exploratory analysis showed clinically meaningful improvements were observed for the vedolizumab every four weeks and every eight weeks groups in GEMINI II and the improvements were significantly greater as compared with the placebo group from baseline to Week 52 on EQ-5D and EQ-5D VAS scores, total IBDQ score, and IBDQ subscales of bowel symptoms and systemic function. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with vedolizumab in one or more subsets of the paediatric population in ulcerative colitis and Crohn's disease (see section 4.2). 5.2 Pharmacokinetic properties The single and multiple dose pharmacokinetics of vedolizumab have been studied in healthy subjects and in patients with moderate to severely active ulcerative colitis or Crohn's disease. In patients administered 300 mg vedolizumab as a 30 minute intravenous infusion on Weeks 0 and 2, mean serum trough concentrations at Week 6 were 27.9 mcg/ml (SD ± 15.51) in ulcerative colitis and 26.8 mcg/ml (SD ± 17.45) in Crohn's disease. Starting at Week 6, patients received 300 mg vedolizumab every eight or four weeks. In patients with ulcerative colitis, mean steady-state serum trough concentrations were 11.2 mcg/ml (SD ± 7.24) and 38.3 mcg/ml (SD ± 24.43), respectively. In patients with Crohn's disease mean steady-state serum trough concentrations were 13.0 mcg/ml (SD ± 9.08) and 34.8 mcg/ml (SD ± 22.55), respectively. Distribution Population pharmacokinetic analyses indicate that the distribution volume of vedolizumab is approximately 5 litres. The plasma protein binding of vedolizumab has not been evaluated. Vedolizumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins. Vedolizumab does not pass the blood brain barrier after intravenous administration. Vedolizumab 450 mg administered intravenously was not detected in the cerebrospinal fluid of healthy subjects. Elimination Population pharmacokinetic analyses indicate that vedolizumab has a total body clearance of approximately 0.157 L/day and a serum half-life of 25 days. The exact elimination route of vedolizumab is not known. Population pharmacokinetic analyses suggest that while low albumin, higher body weight, prior treatment with anti-TNF drugs and presence of anti-vedolizumab antibody may increase vedolizumab clearance, the magnitude of their effects is not considered to be clinically relevant. Linearity Vedolizumab exhibited linear pharmacokinetics at serum concentrations greater than 1 mcg/ml. Special populations Age does not impact the vedolizumab clearance in ulcerative colitis and Crohn's disease patients based on the population pharmacokinetic analyses. No formal studies have been conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of vedolizumab. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, as well as reproductive and development toxicology studies. Long-term animal studies with vedolizumab to assess its carcinogenic potential have not been conducted because pharmacologically responsive models to monoclonal antibodies do not exist. In a pharmacologically responsive species (cynomolgus monkeys), there was no evidence of cellular hyperplasia or systemic immunomodulation that could potentially be associated with oncogenesis in 13- and 26-week toxicology studies. Furthermore, no effects were found of vedolizumab on the proliferative rate or cytotoxicity of a human tumour cell line expressing the α4β7 integrin in vitro. No specific fertility studies in animals have been performed with vedolizumab. No definitive conclusion can be drawn on the male reproductive organs in cynomolgus monkey repeated dose toxicity study, but given the lack of binding of vedolizumab to male reproductive tissue in monkey and human, and the intact male fertility observed in β7 integrin-knockout mice, it is not expected that vedolizumab will affect male fertility. Administration of vedolizumab to pregnant cynomolgus monkeys during most of gestation resulted in no evidence of effects on teratogenicity, prenatal or postnatal development in infants up to 6 months of age. Low levels (<300 mcg/L) of vedolizumab were detected on post-partum Day 28 in the milk of 3 of 11 cynomolgus monkeys treated 100 mg/kg of vedolizumab dosed every 2 weeks and not in any animals that received 10 mg/kg. It is not known whether vedolizumab is excreted in human milk. 6. Pharmaceutical particulars 6.1 List of excipients L-histidine L-histidine monohydrochloride L-arginine hydrochloride sucrose polysorbate 80 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years Chemical and physical in-use stability of the reconstituted and diluted solution has been demonstrated for 12 hours at 20°C-25°C and 24 hours at 2°C-8°C. From a microbiological point of view, the product must be used immediately. Do not freeze the reconstituted or diluted solution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not be longer than a total of 24 hours. This 24 hour hold may include up to 12 hours at 20°C-25°C; any additional hold time must be at 2°C-8°C. 6.4 Special precautions for storage Store in a refrigerator (2°C-8°C). Keep the vial in the outer carton in order to protect from light. For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Entyvio 300 mg powder for concentrate for solution for infusion in Type 1 glass vial (20 ml) fitted with rubber stopper and aluminium crimp protected by a plastic cap. Each pack contains 1 vial. 6.6 Special precautions for disposal and other handling Instructions for reconstitution and infusion Entyvio should be at room temperature (20°C -25°C) when reconstituted. 1. Use aseptic technique when preparing Entyvio solution for intravenous infusion. Remove flip-off cap from the vial and wipe with alcohol swab. Reconstitute vedolizumab with 4.8 ml of sterile water for injection, using a syringe with a 21-25 gauge needle. 2. Insert the needle into the vial through the centre of the stopper and direct the stream of liquid to the wall of the vial to avoid excessive foaming. 3. Gently swirl the vial for at least 15 seconds. Do not vigorously shake or invert. 4. Let the vial sit for up to 20 minutes to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. 5. Inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. Solution should be clear or opalescent, colourless to light yellow and free of visible particulates. Reconstituted solution with uncharacteristic colour or containing particulates must not be administered. 6. Prior to withdrawing reconstituted solution from vial, gently invert vial 3 times. 7. Withdraw 5 ml (300 mg) of reconstituted Entyvio using a syringe with a 21-25 gauge needle. 8. Add the 5 ml (300 mg) of reconstituted Entyvio to 250 ml of sterile 0.9% sodium chloride solution, and gently mix the infusion bag (5 ml of 0.9% sodium chloride solution does not have to be withdrawn from the infusion bag prior to adding Entyvio). Do not add other medicinal products to the prepared infusion solution or intravenous infusion set. Administer the infusion solution over 30 minutes (see section 4.2). Entyvio does not contain preservatives. Once reconstituted, the infusion solution should be used as soon as possible. However, if necessary, the infusion solution may be stored for up to 24 hours: this 24 hour hold may include up to 12 hours at 20°C-25°C; any additional hold time must be at 2°C -8°C. Do not freeze. Do not store any unused portion of the infusion solution for reuse. Each vial is for single-use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Takeda Pharma A/S Dybendal Alle 10 2630 Taastrup Denmark 8. Marketing authorisation number(s) EU/1/14/923/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 22 May 2014 10. Date of revision of the text 22 May 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 单抗药物Entyvio（vedolizumab）获欧盟批准上市 2014年5月27日，武田（Takeda）单抗药物Entyvio（vedolizumab）获欧盟委员会（EC）批准，用于中度至重度活动性溃疡性结肠炎（ulcerative colitis，UC）成人患者及中度至重度克罗恩病（Crohn's disease，CD）成人患者的治疗。在美国，该药已于5月20日获FDA批准。 此前，vedolizumab于2014年3月获得了欧洲药品管理局（EMA）人用医药产品委员会（CHMP）建议批准的积极意见。 Vedolizumab上市许可申请（MAA）的提交，是根据GEMINI项目的汇总数据，该项目包括4个III期研究，这是迄今为止在CD和UC患者中开展的最大的III期临床试验项目，旨在评估vedolizumab用于治疗既往至少经一种常规治疗或TNF-α拮抗剂治疗失败的中度至重度活动性克罗恩病和溃疡性结肠炎患者时，对临床反应、临床缓解、长期安全性的影响。 Vedolizumab是一种全人源化单克隆抗体，特异性拮抗α4β7整合素，抑制α4β7整合素对肠道黏膜细胞粘附分子MAdCAM-1的结合。MAdCAM-1选择性表达于肠胃血管和淋巴结。α4β7整合素表达于一组循环（circulating）白细胞，这些细胞已被证明在CD和UC疾病中介导炎症过程中发挥了重要作用。 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
注射用维多珠单抗|ENTYVIO(vedolizumab infusion)简介：英文药名：ENTYVIO(vedolizumab for solution for infusion)
中文药名：注射用维多珠单抗
生产厂家：Takeda药业德国公司药品介绍2014年3月22日。欧洲人用药品委员会[CHMP]建议批准维多珠单抗 (Entyvi ... 责任编辑：admin |
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