英文药名：Tivicay Tablets（Dolutegravir Sodium） 中文药名：度鲁特韦钠片 生产厂家：Vive Health Care Co.Ltd. テビケイ錠50mg HIV新药Tivicay（dolutegravir）片剂获批准为每日一次的口服药物，是HIV整合酶抑制剂，旨在与其他抗逆转录病毒制剂联合用于既往已治疗过、或初治HIV-1成人和12岁及以上体重至少40千克儿童感染者。 药物分类名称 HIV整合酶抑制剂 批准日期：2014年4月 商標名 Tivicay Tablets 一般名 ドルテグラビルナトリウム （Dolutegravir Sodium） 化学名 Monosodium （4R,12aS）-9-｛［（2,4-difluorophenyl）methyl］carbamoyl｝-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido［1',2'：4,5］pyrazino［2,1-b］［1,3］oxazin-7-olate 分子式 C20H18F2N3NaO5 分子量 441.36 構造式 性状 白色至淡黄白色粉末。难溶于水，几乎不溶于乙醇（99.5）。 熔点 1型晶体在约350℃熔化的同时降解 分配系数 2.16±0.01（23℃） 审批条件 1.使用此药时，请向患者充分解释正在收集有关此药物的进一步有效性/安全性数据，并要求医生取得知情同意书它。 2.对于目前正在进行或计划在国外进行的临床试验，终止后应立即提交检测结果和分析结果。 3.原则上，在复查期结束前，对所有国内的管理案例和实际使用该药的信息进行上市后监督（患者背景，疗效/安全性包括组合时的疗效和安全性）和药物相互作用数据等），定期与报告收集一起，在复试要求的调查结果时应当提交的申请书的附件。 药效药理 1. 作用机序 Doltegravir与HIV整合酶的活性位点结合，该整合酶是逆转录病毒复制所需的酶，并通过在掺入DNA时抑制HIV-DNA链的转移而抑制HIV整合酶。 2.抗病毒作用（体外） 在HIV-1 BaL的应变和感染HIV-1株NL432，Dorutegurabiru的针对病毒增殖的抗病毒活性（IC 50）的50％抑制浓度外周血单核细胞，分别0.51 nM的，为0.53纳米。 当向感染HIV-1 IIIB菌株的MT-4细胞中加入拜尔格韦并培养4天或5天时，抗病毒活性的IC 50分别为0.71nM和2.1nM。而且，在使用纯化的HIV-1整合酶和预处理的底物DNA的链转移生化测定形式中，抗病毒活性的IC 50分别为2.7nM和12.6nM。 在使用来自13个临床不同的B亚型分离株的整合酶编码区的病毒整合酶传染性分析方法中，IC50为0.52nM，并显示出高抗病毒活性。 Doltegravir还显示出与实验菌株相当的抗病毒效果。由24个HIV-1临床分离株[M组（亚型A，B，C，D，E，F，G）和O组]和三个HIV-2临床分离株组成的面板系的外周血在单核细胞分析测试中，HIV-1菌株的IC 50为0.20nM，其范围为0.02至2.14nM。另一方面，HIV-2株的IC 50为0.18nM，其范围为0.09-0.61nM。 3.耐药性 使用Monogram Biosciences的PhenoSense分析测试了30种对raltegravir具有基因型和表型耐药性的临床分离株[倍数变化（FC）> 81]对多索拉维的敏感性（FC = 1.5）。 在G140S + Q148H分离株中，doltegravir的FC值为3.75，G 140 O + Q 148 R分离株为13.3，T 97 A + Y 143 R株为1.05，N 155 H分离株为1.37。 使用Monogram Biosciences的PhenoSense分析检查了从具有raltegravir给药经验的患者中分离的705个raltegravir耐药菌株对多索拉维的敏感性。 Dorothgravir的FC不到10分，而705分为93.9％。 对于有抗HIV药物治疗经验且没有HIV整合酶抑制剂给药经验的患者进行SAILING试验（354 doltetravir给药组），在给药48周后有17例病毒治疗失败 4例患者中有4例观察到对HIV整合酶抑制剂的抗药性。 观察到这4例中2例特有的R263K整合酶突变，FC的最大值为1.93。 在另一个实例中，观察到多态性V151V/I整合酶突变，FC的最大值为0.92，并且在剩余的一个中，整合酶突变在测试前被识别，并且整合酶抑制 据推测，他们曾经服用过该药物或感染过整合酶抗性病毒。 在对HIV整合酶抑制剂耐药的患者的VIKING  -  3试验中，在给药后24周183例患者中有36例观察到病毒学治疗失败。 其中31例分析阻力数据在研究开始时和病毒学治疗失败时存在，31例患者中有16例突变（52％）表现出与施用相关的突变。 （1例），E92Q（2例），T97A（8例），E138K/A（7例），G140S（2例），Y143H ），S147G（1例），Q148H/K/R（4例），N155H（1例）和E157E/Q（1例）。 另外，在治疗中出现突变的16名患者中，有14名在研究开始时或之前出现了Q148突变。 适应病症 HIV感染症 用法与用量 通常以下列剂量和剂量口服给成人。本品可以用或不用餐。 使用时请务必与其他抗HIV药物一起使用。 （1）接受未治疗患者治疗的患者，除整合酶抑制剂以外的抗HIV药物 每日一次口服给予50mg作为多特格韦。 （2）对整合酶抑制剂有抗性的患者 每天两次给予50mg作为多洛特韦。 对于经过抗HIV药物治疗的未经治疗的整合酶抑制剂，年龄在12岁或以上，体重在40公斤或以上的儿科患者，可每天一次口服50mg作为doltegraville。 包装规格 片剂 50毫克：30片（瓶装） 制造商 Vive医疗保健有限公司 注：以上中文资料不够完整，使用者以原处方为准。 完整说明书附件：http://www.info.pmda.go.jp/go/pack/6250038F1023_1_06/ HIV整合酶抑制剂：Tivicay Tablets(Dolutegravir テビケイ錠) Trade name Tivicay Tablets Generic name DESCRIPTION TIVICAY (dolutegravir) Tablets for Oral Use Initial U.S. Approval: 2013 TIVICAY contains dolutegravir, as dolutegravir sodium, an HIV INSTI. The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 g/mol. Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water. Each film-coated tablet of TIVICAY for oral administration contains 52.6 mg of dolutegravir sodium, which is equivalent to 50 mg dolutegravir free acid, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients iron oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. CLINICAL PHARMACOLOGY Mechanism of Action: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM. INDICATIONS AND USAGE: TIVICAY is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children aged 12 years and older and weighing at least 40 kg. The following should be considered prior to initiating TIVICAY: Poor virologic response was observed in subjects treated with TIVICAY 50 mg twice daily with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R. CONTRAINDICATIONS Coadministration with dofetilide is contraindicated PRECAUTIONS WARNINGS AND PRECAUTIONS: 1. Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. TIVICAY should not be used in patients who have experienced a previous hypersensitivity reaction to TIVICAY. 2.Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY is recommended in patients with underlying hepatic disease such as hepatitis B or C. 3.Redistribution/accumulation of body fat and immune reconstitution syndrome have been reported in patients treated with combination antiretroviral therapy. ADVERSE REACTIONS ADVERSE REACTIONS: The most common adverse reactions of moderate to severe intensity and incidence 2% (in those receiving TIVICAY in any one adult trial) are insomnia and headache. To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS: Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. TIVICAY should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications. USE IN SPECIFIC POPULATIONS: Pregnancy: TIVICAY should be used during pregnancy only if the potential benefit justifies the potential risk. Nursing mothers: Breastfeeding is not recommended due to the potential for HIV transmission. Pediatric patients: Safety and efficacy of TIVICAY have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION: May be taken without regard to meals. Adult Population: Recommended Dose: 1] Treatment-naïve or treatment-experienced INSTI-naïve: 50 mg once daily 2] Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with the following potent UGT1A/CYP3A inducers: efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin: 50 mg twice daily 3] INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance: 50 mg twice daily. Alternative combinations that do not include metabolic inducers should be considered where possible. Pediatric Patients: (Treatment-naïve or treatment-experienced, INSTI-naïve, aged 12 years and older, and weighing at least 40 kg). 1] The recommended dose is TIVICAY 50 mg once daily. 2] If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are coadministered, then the dose is TIVICAY 50 mg twice daily HOW SUPPLIED DOSAGE FORMS AND STRENGTHS: Tablets: 50mg Tivicay®(dolutegravir)Tablets 50 mg 30Tablets Rx Only Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg of dolutegravir. Store at controlled room temperature of 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP).