部份中文替度鲁肽处方资料(仅供参考)
Description of selected adverse reactions Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Revestive may potentially trigger the development of antibodies. In phase 3 studies with SBS patients who received Revestive for ≥ 2 years, 39% of patients developed anti-teduglutide antibodies and 21% of patients developed antibodies against E.coli protein (residual host cell protein from the manufacture). The antibody formation has not been associated with clinically relevant safety findings, reduced efficacy or changed pharmacokinetics of Revestive. Injection site reactions Injection site reactions occurred in 21% of SBS patients treated with Revestive. The reactions appeared to be dose dependent and occurred with similar frequency in patients given the recommended dose of 0.05 mg/kg/day Revestive and in patients given placebo (injection site reactions were experienced by 12% of the placebo-treated patients, by 13% of the patients who received 0.05 mg/kg/day Revestive and by 41% of the patients who received 0.10 mg/kg/day Revestive). The reactions included injection site erythema, injection site haematoma and injection site pain (see also section 5.3). C-reactive protein Modest increases of C-reactive protein of approximately 25 mg/l have been observed within the first seven days of Revestive treatment, which decreased continuously under ongoing daily injections. After 24 weeks of Revestive treatment, patients showed small overall increase in C-reactive protein of approximately 1.5 mg/l on average. These changes were neither associated with any changes in other laboratory parameters nor with any reported clinical symptoms. There were no clinically relevant mean increases of C-reactive protein from baseline following long-term treatment with Revestive for up to 30 months. 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 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 United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose The maximum dose of teduglutide studied during clinical development was 86 mg/day for 8 days. No unexpected systemic adverse reactions were seen (see section 4.8). In the event of an overdose, the patient should be carefully monitored by the medical professional. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products, ATC code: A16AX08. Mechanism of action The naturally occurring human glucagon-like peptide-2 (GLP-2) is a peptide secreted by L cells of the intestine which is known to increase intestinal and portal blood flow, inhibit gastric acid secretion, and decrease intestinal motility. Teduglutide is an analogue of GLP-2. In several nonclinical studies, teduglutide has been shown to preserve mucosal integrity by promoting repair and normal growth of the intestine through an increase of villus height and crypt depth. Pharmacodynamic effects Similar to GLP-2, teduglutide is 33 amino acids in length with an amino acid substitution of alanine by glycine at the second position of the N-terminus. The single amino acid substitution relative to naturally occurring GLP-2 results in resistance to in vivo degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in an extended half-life. Teduglutide increases villus height and crypt depth of the intestinal epithelium. Based on the concerns derived from pre-clinical studies (see section 5.3) and the proposed mechanism of action with the trophic effects on intestinal mucosa, there appears to be a risk for the promotion of small intestinal and/or colonic neoplasia. The clinical studies conducted could neither exclude nor confirm such an increased risk. Several cases of benign colonic polyps occurred during the course of the trials, however, the frequency was not increased compared to placebo-treated patients. In addition to the need for a colonoscopy with removal of polyps by the time of the initiation of the treatment (see section 4.4.), every patient should be assessed for the need of an enhanced surveillance schedule based on the patient characteristics (e.g. age and underlying disease, previous occurrence of polyps etc.). Clinical efficacy Revestive was studied in 17 patients with SBS allocated to five treatment groups using doses of 0.03, 0.10 or 0.15 mg/kg teduglutide once daily, or 0.05 or 0.075 mg/kg bid in a 21-day open-label, multicenter, dose-ranging study. Treatment resulted in enhanced gastrointestinal fluid absorption of approximately 750-1000 ml/day with improvements in the absorption of macronutrients and electrolytes, decreased stomal or faecal fluid and macronutrients excretion, and enhanced key structural and functional adaptations in the intestinal mucosa. Structural adaptations were transient in nature and returned to baseline levels within three weeks of discontinuing the treatment. In the pivotal phase 3 double-blind, placebo-controlled study in patients with SBS, who required parenteral nutrition, 43 patients were randomised to a 0.05 mg/kg/day dose of Revestive and 43 patients to placebo for up to 24 weeks. The proportion of Revestive-treated subjects achieving a 20% to 100% reduction of parenteral nutrition at Week 20 and 24 was statistically significantly different from placebo (27 out of 43 subjects, 62.8% versus 13 out of 43 patients, 30.2%, p=0.002). Treatment with Revestive resulted in a 4.4 l/week reduction in parenteral nutrition requirements (from a pre-treatment baseline of 12.9 litres) versus 2.3 l/week (from a pre-treatment baseline of 13.2 litres) for placebo at 24 weeks. Twenty-one patients treated with Revestive (48.8%) versus 9 on placebo (20.9%) achieved at least a one day reduction in parenteral nutrition administration (p=0.008). Ninety-seven percent of patients (37 out of 39 patients treated with teduglutide) that completed the placebo-controlled study entered a long-term extension study where all patients received 0.05 mg/kg of Revestive daily for up to an additional 2 years. In total 88 patients participated in this extension study, thereof 39 treated with placebo and 12 enrolled, but not randomised, in the previous study; 65 of 88 patients completed the extension study. There continued to be evidence of increased response to treatment for up 2.5 years in all groups exposed to Revestive in terms of parenteral nutrition volume reduction, gaining additional days off parenteral nutrition per week, and achieving weaning of parenteral support. Thirty (30) of the 43 Revestive-treated patients from the pivotal study who entered the extension study completed a total of 30 months of treatment. Of these, 28 patients (93%) achieved a 20% or greater reduction of parenteral support. Of responders in the pivotal study who completed the extension study, 21 out of 22 (96%) sustained their response to Revestive after an additional 2 years of continuous treatment. The mean reduction in parenteral nutrition (n=30) was 7.55 l/week (a 65.6% reduction from baseline). Ten subjects were weaned off their parenteral support while on Revestive treatment for 30 months. Subjects were maintained on Revestive even if no longer requiring parenteral nutrition. These 10 subjects had required parenteral nutrition support for 1.2 to 15.5 years, and prior to treatment with Revestive had required between 3.5 l/week and 13.4 l/week of parenteral nutrition support. At the end of study, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved a reduction of 1, 2, or 3 days per week in parenteral support, respectively. Of the 39 placebo subjects, 29 completed 24 months of treatment with Revestive. The mean reduction in parenteral nutrition was 3.11 l/week (an additional 28.3% reduction). Sixteen (55.2%) of the 29 completers achieved a 20% or greater reduction of parenteral nutrition. At the end of study, 14 (48.3%), 7 (24.1%) and 5 (17.2%) patients achieved a reduction of 1, 2, or 3 days per week in parenteral nutrition, respectively. Two subjects were weaned off their parenteral support while on Revestive. Of the 12 subjects not randomised in the pivotal study, 6 completed 24 months of treatment with Revestive. The mean reduction in parenteral nutrition was 4.0 l/week (39.4% reduction from baseline – the start of the extension study) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction in parenteral support. At the end of study, 3 (50%), 2 (33%) and 2 (33%) achieved a reduction of 1, 2, or 3 days per week in parenteral nutrition, respectively. One subject was weaned off their parenteral support while on Revestive. In another phase 3 double-blind, placebo-controlled study in patients with SBS, who required parenteral nutrition, patients received a 0.05 mg/kg/day dose (n = 35), a 0.10 mg/kg/day dose (n = 32) of teduglutide or placebo (n = 16) for up to 24 weeks. The primary efficacy analysis of the study results showed no statistically significant difference between the group on teduglutide 0.10 mg/kg/day and the placebo group, while the proportion of subjects receiving the recommended teduglutide dose of 0.05 mg/kg/day achieving at least a 20% reduction of parenteral nutrition at Week 20 and 24 was statistically significantly different versus placebo (46% versus 6.3%, p<0.01). Treatment with Revestive resulted in a 2.5 l/week reduction in parenteral nutrition requirements (from a pre-treatment baseline of 9.6 litres) versus 0.9 l/week (from a pre-treatment baseline of 10.7 litres) for placebo at 24 weeks. Revestive treatment induced expansion of the absorptive epithelium by significantly increasing villus height in the small intestine. Sixty-five patients entered a follow-up SBS study for up to an additional 28 weeks of treatment. Patients on Revestive maintained their previous dose assignment throughout the extension phase, while placebo patients were randomised to active treatment, either 0.05 or 0.10 mg/kg/day. Of the patients who achieved at least a 20% reduction of parenteral nutrition at Weeks 20 and 24 in the initial study, 75% sustained this response on Revestive after up to 1 year of continuous treatment. The mean reduction of weekly parenteral nutrition volume was 4.9 l/week (52% reduction from baseline) after one year of continuous teduglutide treatment. Two patients on the recommended teduglutide dose were weaned off parenteral nutrition by Week 24. One additional patient in the follow-up study was weaned off parenteral nutrition. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Revestive in one or more subsets of the paediatric population in the treatment of SBS (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Teduglutide was rapidly absorbed from subcutaneous injection sites with maximum plasma levels occurring approximately 3-5 hours after dose administration at all dose levels. The absolute bioavailability of subcutaneous teduglutide is high (88%). No accumulation of teduglutide was observed following repeated subcutaneous administration. Distribution Following subcutaneous administration, teduglutide has an apparent volume of distribution of 26 litres in patients with SBS. Biotransformation The metabolism of teduglutide is not fully known. Since teduglutide is a peptide it is likely that it follows the principal mechanism for peptide metabolism. Elimination Teduglutide has a terminal elimination half-life of approximately 2 hours. Following intravenous administration teduglutide plasma clearance was approximately 127 ml/hr/kg which is equivalent to the glomerular filtration rate (GFR). Renal elimination was confirmed in a study investigating pharmacokinetics in subjects with renal impairment. No accumulation of teduglutide was observed following repeated subcutaneous administrations. Dose linearity The rate and extent of absorption of teduglutide is dose-proportional at single and repeated subcutaneous doses up to 20 mg. Pharmacokinetics in subpopulations Gender No clinically relevant gender differences were observed in clinical studies. Elderly In a phase 1 study no difference in pharmacokinetics of teduglutide could be detected between healthy subjects younger than 65 years versus older than 65 years. Experience in subjects 75 years and above is limited. Hepatic impairment In a phase 1 study the effect of hepatic impairment on the pharmacokinetics of teduglutide following subcutaneous administration of 20 mg teduglutide was investigated. The maximum exposure and the overall extent of exposure to teduglutide following single 20 mg subcutaneous doses were lower (10-15%) in subjects with moderate hepatic impairment relative to those in healthy matched controls. Renal impairment In a phase 1 study, the effect of renal impairment on the pharmacokinetics of teduglutide following subcutaneous administration of 10 mg teduglutide was investigated. With progressive renal impairment up to and including end stage renal disease the primary pharmacokinetic parameters of teduglutide increased up to a factor of 2.6 (AUCinf) and 2.1 (Cmax) compared to healthy subjects. 5.3 Preclinical safety data Hyperplasia in the gall bladder, hepatic biliary ducts, and pancreatic ducts were observed in subchronic and chronic toxicology studies. These observations were potentially associated with the expected intended pharmacology of teduglutide and were to a varying degree reversible within an 8-13 week recovery period following chronic administration. Injection site reactions In pre-clinical studies, severe granulomatous inflammations were found associated with the injection sites. Carcinogenicity / mutagenicity Teduglutide was negative when tested in the standard battery of tests for genotoxicity. In a rat carcinogenicity study, treatment related benign neoplasms included tumours of the bile duct epithelium in males exposed to teduglutide plasma levels approximately 32- and 155-fold higher than obtained in patients administered the recommended daily dose (incidence of 1 out of 44 and 4 out of 48, respectively). Adenomas of the jejunal mucosa were observed in 1 out of 50 males and 5 out of 50 males exposed to teduglutide plasma levels approximately 10- and 155-fold higher than obtained in patients administered the recommended daily dose. In addition, a jejunal adenocarcinoma was observed in a male rat administered the lowest dose tested (animal:human plasma exposure margin of approximately 10-fold). Reproductive and developmental toxicity Reproductive and developmental toxicity studies evaluating teduglutide have been carried out in rats and rabbits at doses of 0, 2, 10 and 50 mg/kg/day subcutaneously. Teduglutide was not associated with effects on reproductive performance, in utero or developmental parameters measured in studies to investigate fertility, embryo-fetal development and pre- and post-natal development. Pharmacokinetic data demonstrated that the teduglutide exposure of fetal rabbits and suckling rat pups was very low. 6. Pharmaceutical particulars 6.1 List of excipients Powder L-histidine Mannitol Sodium phosphate monohydrate Disodium phosphate heptahydrate Sodium hydroxide (pH adjustment) Hydrochloric acid (pH adjustment) Solvent Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 4 years. After reconstitution, from a microbiological point of view, the solution should be used immediately. However, chemical and physical stability has been demonstrated for 3 hours at 25°C. 6.4 Special precautions for storage Store below 25°C. Do not freeze. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 5 mg teduglutide powder in vial (glass) with rubber stopper (bromobutyl). 0.5 ml of solvent in pre-filled syringe (glass) and plungers (plastic) for assembly with the pre-filled syringe. Pack size of 28 vials of powder, 28 pre-filled syringes and 6 plungers. 6.6 Special precautions for disposal and other handling Determination of the number of vials needed for administration of one dose must be based on the individual patient's weight and the recommended dose of 0.05 mg/kg/day (see injection volumes in the table below). The physician should at each visit weigh the patient, determine the daily dose to be administered until next visit and inform the patient accordingly. A table with the injection volume per body weight is provided below:
The powder in the vial must then be dissolved by adding all the solvent from the pre-filled syringe. The vial should not be shaken, but can be rolled between the palms and gently turned upside-down once. Once a clear colourless solution is formed in the vial, the solution should be sucked up into a 1 ml injection syringe with scale intervals of 0.02 ml or smaller (not included in the pack). If two vials are needed, the procedure for the second vial must be repeated and the additional solution sucked up into the injection syringe containing the solution from the first vial. Any volume exceeding the prescribed dose in ml must be expelled and discarded. The solution must be injected subcutaneously into a cleaned area on the abdomen, or if this is not possible, on the thigh (see section 4.2 Method of administration) using a thin needle for subcutaneous injection. Detailed instructions on the preparation and injection of Revestive are provided in the package leaflet. The solution must not be used if it is cloudy or contains particulate matter. For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. All needles and syringes should be disposed of in a sharps disposal container. 7. Marketing authorisation holder NPS Pharma Holdings Limited 5 Riverwalk Citywest Business Campus Dublin 24 Ireland Tel.: +800 6774 4357 8. Marketing authorisation number(s) EU/1/12/787/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 30 August 2012 10. Date of revision of the text 08/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 武田Revestive获欧盟委员会批准用于短肠综合征(SBS)治疗 2012年9月5日,武田(Takeda)制药与其合作伙伴NPS制药公司宣布,药物Revestive(teduglutide)上市许可申请(MAA)已获欧盟委员会批准,作为日服一次的药物用于短肠综合征(short bowel syndrome,SBS)成人患者的治疗。 在今年6月21日,Revestive的上市许可申请(MAA)已获欧洲药品管理局(EMA)人用医药产品委员会(CHMP)积极意见。 武田最初将通过NPP项目(Named Patient Program)向欧洲的患者提供Revestive。 “短肠综合征(SBS)患者遭受营养不良和腹泻,并经常需要胃肠外营养支持来维持生命,”丹麦哥本哈根大学医学院消化内科Palle Bekker Jeppesen医师说道。“对于我们的患者来说,Revestive是一种新颖、独特、重要的治疗选择,同时为有限的治疗医疗设备增加了重要的价值。” |
Revestive injection(替度多西特粉末/注射溶液)简介:
部份中文Revestive处方资料(仅供参考)商品名:Revestive通用名:teduglutide活性物质:teduglutide药物治疗组:其他消化道和新陈代谢产品治疗适应症Revestive为成年患者短肠综合征的治疗。患者应在手 ... 责任编辑:admin
|
最新文章更多推荐文章更多热点文章更多
|