药品别名 护肝素、脱氧熊胆酸、乌素脱氧胆酸、熊脱氧胆酸、优思弗、AcidumUrsodesoxycholicum、UDCA、Ursacol、URSO、Ursofalk、Ulmenid 药物剂型 1.片剂：50mg，150mg； 2.胶囊：250mg。 药理作用 熊去氧胆酸(UDCA)为正常胆汁中初级胆汁酸鹅去氧胆酸的7-β异构体，具有以下作用特点： 1.增加胆汁酸的分泌，导致胆汁酸成分的变化，使其在胆汁中含量增加，有利胆作用。患者服用后胆汁酸分泌均值由每小时1.8mmol增至2.24mmol，长期服用可增加UDCA在胆汁中的含量，不增加胆酸的含量。 2.能抑制肝脏胆固醇的合成，显著降低胆汁中胆固醇及胆固醇酯的量和胆固醇的饱和指数，从而有利于结石中胆固醇逐渐溶解。此外，UDCA还能促进液态胆固醇晶体复合物形成，后者可加速胆固醇从胆囊向肠道排泄清除。 3.松弛奥迪(Oddi)括约肌，有利胆作用。 4.减少肝脏脂肪，增加肝脏过氧化氢酶的活性，促进肝糖原的蓄积，提高肝脏抗毒、解毒能力。 5.可降低肝脏和血清中三酰甘油的浓度。 6.抑制消化酶、消化液的分泌。 7.国外研究亦表明熊去氧胆酸在慢性肝脏疾病中具有免疫调节作用，能明显降低肝细胞HLAI类抗原的表达，降低活化T细胞的数目。本药在体内溶解胆固醇结石的效果优于鹅去氧胆酸(CDCA)。 药动学 本药呈弱碱性，口服后通过被动扩散而迅速吸收，吸收的最有效部位是中等碱性环境的回肠。生物利用度为90%，总蛋白结合率为70%。本药通过肝脏时被摄取5%～60%，明显低于鹅去氧胆酸，仅少量药物进入体循环，血药浓度很低。口服后1h和3h分别出现两个血药浓度峰值。 用于溶解胆石时，口服后3～6个月起效。本药的治疗作用不取决于血药浓度而与胆汁中的药物浓度有关。半衰期为3.5～5.8天。本药在肝脏与甘氨酸或牛磺酸迅速结合，从胆汁排入小肠，参加肝肠循环。小肠内结合的熊去氧胆酸一部分水解回复为游离型，另一部分在细菌作用下转变为石胆酸(Lithocholic Acid)，后者进而被硫酸化，从而降低其潜在的肝脏毒性。 本药主要随粪便排出，少量经肾排泄。本药是否经人乳汁排泄尚不清楚。由于口服后仅少量经肾排泄。本药是否经人乳汁排泄尚不清楚。由于口服后仅少量熊去氧胆酸出现在血清中，所以如果乳汁中有的话，其量也非常少。 适应证 1.主要用于不宜手术治疗的胆固醇型胆结石：适用于胆囊功能正常、透光、直径10～15mm的非钙化结石。 2.预防胆结石形成：需长期用易形成胆固醇结石的药物(如雌激素、氯贝丁酯及其衍生物、考来烯胺)的患者、长期进食高胆固醇饮食者、或有易感遗传因素者，均可服用本药预防胆结石形成。 3.治疗胆囊炎、胆管炎、胆汁性消化不良、黄疸等。 4.治疗回肠切除术后脂肪泻、高三酰甘油血症、肝大、慢性肝炎，亦可用于胆汁反流性胃炎。 5.还用于原发性胆汁性肝硬化和原发性硬化性胆管炎。 禁忌证 1.严重肝炎及严重肝功能减退者。 2.胆道完全阻塞者。 3.胃、十二指肠溃疡及其他肠道疾病者。 4.对胆汁酸过敏者。 5.有胆囊切除术指征的患者，包括持续性急性胆囊炎、胆管炎、胆石性胰腺炎或胆道胃肠瘘。 6.孕妇、儿童、哺乳妇女禁用。 注意事项 本药不能溶解胆色素结石、钙化胆固醇性结石、混合结石及不透过X线结石。 不良反应 本药的毒性和不良反应比鹅去氧胆酸小。 1.胃肠道：主要为腹泻，发生率约为2%。偶见便秘、胃痛、胰腺炎等。 2.肝毒性：本药对肝脏毒性不明显。 3.呼吸系统：国外资料报道，可出现支气管炎、咳嗽、咽炎等呼吸系统的不良反应。 4.中枢神经系统：偶见头痛、头晕等。 5.皮肤：可出现瘙痒、脱发等。 6.肌肉骨骼：可出现关节痛、关节炎、背痛和肌痛等。 7.致癌及致突变作用：动物实验未发现本药有致突变作用，光镜和电镜下观察未发现肝细胞与本药一起孵化后有结构上的改变。动物试验(小鼠和大鼠)表明，本药用到最大剂量的5.4倍也不会致癌。 8.其他：偶见过敏、心动过缓、心动过速等。 用法用量 口服给药： 1.利胆：每次50mg，每天150mg。 2.溶解胆结石：每天450～600mg，或每天8～10mg/kg，分早晚2次服。当胆石清除后，每晚口服500mg，以防止复发。 3.肝大、慢性肝炎：每天8～13mg/kg，疗程为6～24个月。 4.胆汁反流性胃炎：每天1000mg，分2次服。 药物相应作用 1.本药与鹅去氧胆酸合用，胆汁中胆固醇的含量和饱和度的降低程度均大于两药单独使用，也大于两药的相加作用。这可能与两药对胆固醇的合成、代谢和溶解动力学的不同作用机制有关。 2.口服避孕药可增加胆汁饱和度，影响本药疗效，故用本药治疗时应采取其他节育措施。 3.药用炭在体外试验中能结合胆汁酸，故与本药联用时会影响后者的吸收。 4.含铝抗酸药在体外试验中能吸附胆汁酸，故与本药联用时可减少本药的吸收。 5.因为考来烯胺、考来替泊在体外试验中均能结合胆汁酸，故与本药联用时可干扰后者的吸收。 专家点评 本品既往用于治疗胆结石病，可溶解胆固醇结石，现还用于治疗胆汁淤积性疾病。国产熊去氧胆酸欠纯，其中含有鹅去氧胆酸，可溶解胆石，但对肝细胞的保护作用远不如UDCA，临床用于肝细胞胆汁淤积，其效用似不如国外报道那样好。对非钙化型的浮动胆固醇结石有较高的治愈率。   DESCRIPTION URSO 250® (ursodiol, 250 mg) and URSO Forte™ (ursodiol, 500 mg) are available as film-coated tablets for oral administration. Ursodiol (ursodeoxycholic acid, UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water. The chemical name of ursodiol is 3(alpha),7(beta)-dihydroxy-5(beta)-cholan-24-oic (C 24 H 40 O 4 ). Ursodiol has a molecular weight of 392.56. Its structure is shown below. Inactive ingredients:   microcrystalline cellulose, povidone, sodium starch glycolate, magnesium stearate, ethylcellulose, dibutyl sebacate, carnauba wax, hydroxypropyl methylcellulose, PEG 3350, PEG 8000, cetyl alcohol, sodium lauryl sulfate and hydrogen peroxide. CLINICAL PHARMACOLOGY Ursodiol (UDCA) is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of ursodiol is absorbed by passive diffusion and its absorption is incomplete. Once absorbed, ursodiol undergoes hepatic extraction to the extent of about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, ursodiol is conjugated with glycine or taurine, then secreted into bile. These conjugates of ursodiol are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some ursodiol is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. Lithocholic acid, when administered chronically to animals, causes cholestatic liver injury that may lead to death from liver failure in certain species unable to form sulfate conjugates. Ursodiol is 7-dehydroxylated more slowly than chenodiol. For equimolar doses of ursodiol and chenodiol, steady state levels of lithocholic acid in biliary bile acids are lower during ursodiol administration than with chenodiol administration. Humans and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals. Nonetheless, such a deficiency has not yet been clearly demonstrated and must be extremely rare, given the several thousand patient-years of clinical experience with ursodiol. In healthy subjects, at least 70% of ursodiol (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated ursodiol to plasma protein in healthy subjects or primary biliary cirrhosis (PBC) patients. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1% except in severe cholestatic liver disease. During chronic administration of ursodiol, it becomes a major biliary and plasma bile acid. At a chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids. CLINICAL STUDIES A U.S., multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of ursodeoxycholic acid at a dose of 13 to 15 mg/kg/day, administered in 3 or 4 divided doses in 180 patients with PBC (78% received QID dosage). Upon completion of the double-blind portion, all patients entered an open-label active treatment extension phase. Treatment failure, the main efficacy end point measured during this study, was defined as death, need for liver transplantation, histologic progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal. After two years of double-blind treatment, the incidence of treatment failure was significantly reduced in the URSO 250® group (n=89) as compared to the placebo group (n=91). Time to treatment failure was also significantly delayed in the URSO 250® treated group regardless of either histologic stage or baseline bilirubin levels (>1.8 or </=1.8 mg/dl). Using a definition of treatment failure which excluded doubling of serum bilirubin and voluntary withdrawal, time to treatment failure was significantly delayed in the URSO 250® group. In comparison with placebo, treatment with URSO 250® resulted in a significant improvement in the following serum hepatic biochemistries when compared to baseline: total bilirubin, SGOT, alkaline phosphatase and IgM. A second study conducted in Canada randomized 222 PBC patients to ursodiol, 14 mg/kg/day or placebo, administered as a once daily dose in a double-blind manner during a two-year period. At two years, a statistically significant difference between the two treatments, in favor of ursodiol, was demonstrated in the following: reduction in the proportion of patients exhibiting a more than 50% increase in serum bilirubin; median percent decrease in bilirubin, transaminases and alkaline phosphatase; incidence of treatment failure; and time to treatment failure. The definition of treatment failure included: discontinuing the study for any reason; a total serum bilirubin level greater than or equal to 1.5 mg/dl or increasing to a level equal to or greater than two times the baseline level; and the development of ascites or encephalopathy. Evaluation of patients at 4 years or longer was inadequate due to the high drop out rate and small number of patients. Therefore, death, need for liver transplantation, histological progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritis, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal were not assessed. A randomized, two-period crossover study in fifty PBC patients compared efficacy of URSO 250® (ursodiol) in BID (two) versus QID (four) divided dosing schedules in 50 patients for 6 months in each crossover period. Mean percent changes from baseline in liver test results and Mayo risk score (n = 46) and serum enrichment with UDCA (n=34) were not statistically significant with any dosage at any time interval. This study demonstrated that UDCA (13 to 15 mg/kg/day) given BID is equally effective to UDCA given QID. In addition, URSO 250® was given as a single (once daily) versus TID (three) dosing schedules in 10 patients. Due to the small number of patients in this arm of the study, it was not possible to conduct statistical comparisons between these regimens. INDICATIONS AND USAGE URSO 250® and URSO Forte™ (ursodiol) tablets are indicated for the treatment of patients with primary biliary cirrhosis. CONTRAINDICATIONS Hypersensitivity or intolerance to ursodiol or any of the components of the formulation. PRECAUTIONS Patients with variceal bleeding, hepatic encephalopathy, ascites or in need of an urgent liver transplant, should receive appropriate specific treatment. Drug Interactions Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of URSO 250® and URSO Forte™ by reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids in vitro and may be expected to interfere with URSO 250® and URSO Forte™ in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of URSO 250® and URSO Forte™ . Carcinogenicity, Mutagenicity and Impairment of Fertility In two 24-month oral carcinogenicity studies in mice, ursodiol at doses up to 1,000 mg/kg/day (3,000 mg/m 2 /day) was not tumorigenic. Based on body surface area, for a 50 kg person of average height (1.46 m 2 body surface area), this dose represents 5.4 times the recommended maximum clinical dose of 15 mg/kg/day (555 mg/m 2 /day). In a two-year oral carcinogenicity study in Fischer 344 rats, ursodiol at doses up to 300 mg/kg/day (1,800 mg/m 2 /day, 3.2 times the recommended maximum human dose based on body surface area) was not tumorigenic. In a life-span (126-138 weeks) oral carcinogenicity study, Sprague-Dawley rats were treated with doses of 33 to 300 mg/kg/day, 0.4 to 3.2 times the recommended maximum human dose based on body surface area. Ursodiol produced a significantly (p</=0.5, Fisher's exact test) increased incidence of pheochromocytomas of the adrenal medulla in females of the highest dose group. In 103-week oral carcinogenicity studies of lithocholic acid, a metabolite of ursodiol, doses up to 250 mg/kg/day in mice and 500 mg/kg/day in rats did not produce any tumors. In a 78-week rat study, intrarectal instillation of lithocholic acid (1 mg/kg/day) for 13 months did not produce colorectal tumors. A tumor-promoting effect was observed when it was administered after a single intrarectal dose of a known carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. On the other hand, in a 32-week rat study, ursodiol at a daily dose of 240 mg/kg (1,440 mg/m 2 , 2.6 times the maximum recommended human dose based on body surface area) suppressed the colonic carcinogenic effect of another known carcinogen azoxymethane. Ursodiol was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK +/- ) forward mutation test, the human lymphocyte sister chromatid exchange test, the mouse spermatogonia chromosome aberration test, the Chinese hamster micronucleus test and the Chinese hamster bone marrow cell chromosome aberration test. Ursodiol at oral doses of up to 2,700 mg/kg/day (16,200 mg/m 2 /day, 29 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy, Teratogenic Effects. Pregnancy Category B Teratology studies have been performed in pregnant rats at oral doses up to 2,000 mg/kg/day (12,000 mg/m 2 /day, 22 times the recommended maximum human dose based on body surface area) and in pregnant rabbits at oral doses up to 300 mg/kg/day (3,600 mg/m 2 /day, 7 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to ursodiol. There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether ursodiol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when URSO 250® and URSO Forte™ are administered to a nursing mother. Pediatric Use The safety and effectiveness of URSO 250® and URSO Forte™ in pediatric patients have not been established. ADVERSE EVENTS (AEs) The following table summarizes the AEs observed in the two placebo-controlled clinical trials. ADVERSE EVENTS VISIT AT 12 MONTHS VISIT AT 24 MONTHS   UDCA n (%) Placebo n (%) UDCA n (%) Placebo n (%) Diarrhea -- -- 1 (1.32) -- Elevated creatinine -- -- 1 (1.32) -- Elevated blood glucose 1 (1.18) -- 1 (1.32) -- Leukopenia -- -- 2 (2.63) -- Peptic ulcer -- -- 1 (1.32) -- Skin rash -- -- 2 (2.63) -- Note: Those AEs occurring at the same or higher incidence in the placebo as in the UDCA group have been deleted from this table (this includes diarrhea and thrombocytopenia at 12 months, nausea/vomiting, fever and other toxicity) UDCA = Ursodeoxycholic acid = Ursodiol In a randomized, cross-over study in sixty PBC patients, four patients (6.7%) experienced one serious adverse event each (diabetes mellitus, cyst and breast neoplasm (experienced by two patients)). No deaths occurred in the study. Forty-three patients (43, 71.7%) experienced at least one treatment-emergent adverse event (TEAEs) during the study. The most common (>5%) TEAEs were asthenia (11.7%), dyspepsia (10%), peripheral edema (8.3%), hypertension (8.3%), nausea (8.3%), GI disorders (5%), chest pain (5%), and puritius (5%). Seven patients (11.6%) reported nine events that were judged as possibly or probably related to study medication. These nine TEAEs included abdominal pain and asthenia (1 patient), nausea (3 patients), dyspepsia (2 patients) and anorexia and esophagitis (1 patient each). One patient on the BID regimen (total dose 1000 mg) withdrew due to nausea. All of these nine TEAEs except esophagitis were observed with the BID regimen at a total daily dose of 1000 mg or greater. OVERDOSE Accidental or intentional overdosage with ursodiol has not been reported. The most severe manifestation of overdosage would likely consist of diarrhea which should be treated symptomatically. Single oral doses of ursodiol at 10, 5 and 10 g/kg in mice, rats and dogs, respectively, were not lethal. A single oral dose of ursodiol at 1.5 g/kg was lethal in hamsters. Symptoms of acute toxicity were salivation and vomiting in dogs, and ataxia, dyspnea, ptosis, agonal convulsions and coma in hamsters. DOSAGE AND ADMINISTRATION The recommended adult dosage for URSO 250® and URSO Forte™ in the treatment of PBC is 13-15 mg/kg/day administered in two to four divided doses with food. Dosing regimen should be adjusted according to each patient's need at the discretion of the physician. HOW SUPPLIED Each URSO 250® elliptical, biconvex, film-coated tablet, white, engraved with "URS785", contains 250 mg of ursodiol. Available in bottles of 100 tablets (NDC 58914-785-10) and 500 tablets (NDC 58914-785-50). Each URSO Forte™ elliptical, biconvex, film-coated tablet, white, engraved with "URS790", contains 500 mg of ursodiol. Available in bottles of 100 tablets (NDC 58914-790-10) and 500 tablets (NDC 58914-790-50). Store at 20°C to 25°C (68°F to 77°F). Dispense in a tight container. ----------------------------------------------- 产地国家: 美国 原产地英文商品名: URSO FORTE 原产地英文药品名: URSODIOL 中文参考商品译名: 熊去氧胆酸 中文参考药品译名: 熊去氧胆酸 生产厂家中文参考译名: APTALIS PHARMA US 生产厂家英文名: APTALIS PHARMA US