英文药名: Actigall(Ursodiol Tablets)

中文药名: 熊去氧胆酸片和胶囊

药品名称

通用名称：熊去氧胆酸
英文名：Ursodeoxycholic Acid
其他中文名：熊脱氧胆酸
其他英文名：Destolit、Ulmenid、Ursacol、Ursochol、Ursodesoxycholic Acid、Ursodiol
剂型: 胶囊/片剂
药理

药效学
胆固醇结石为代谢性结石，由于胆汁内胆固醇浓度增高和缺乏足够的胆盐和磷脂维持其胶粒液相能力，胆固醇呈过饱和状态而形成结石。熊去氧胆酸(UDCA)可促进胆汁分泌, 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 在胆汁中含量, 不增加胆酸的含量。UDCA可使恒河猴及饲以胆固醇加雌激素食物的仓鼠肝中甲基戊二酰辅酶A还原酶的活性降低,因而乙酸盐在肝内转化成胆固醇的速度减慢, 能显著降低人胆汁中胆固醇及胆固醇酯的量和胆固醇的饱和指数。上述作用增加胆固醇在胆汁中的溶解度，使胆固醇溶解和防止结石的形成。

药动学

熊去氧胆酸系弱酸，当发生微胶粒聚集时，其pKa 值约为6.0。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。通过肝脏时被摄取50～60％， 显著低于鹅去氧胆酸(DCDA), 仅少量药物进入体循环。口服后1小时和3小时分别出现两个血药浓度峰值。UDCA的作用不取决于血药浓度而与胆汁中的药浓度有关。半衰期为3.5～5.8天。UDCA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UDCA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(lithocholioacid, LCA), 后者进而被硫酸盐化, 从而降低其潜在的肝脏毒性。
 
适应症　　

有利胆作用，用于治疗胆固醇结石，预防药物性结石形成及治疗脂肪痢（回肠切除术后）。
用法用量　　

口服每日按体重 8?10mg/kg，肥胖者需每日 15mg/kg，进食时分 2次给予。6～12个月为一疗程。
口服，利胆， 1次 50mg， 1日 150mg。早、晚进餐时分次给予。疗程最短为 6个月，6个月后超声波检查及阻囊造影无改善者可停药；如结石已有部分溶解则继续服药直至结石完全溶解。如治疗中有反复胆绞痛发作，症状无改善甚至加重，或出现明显结石钙化时，则宜中止治疗，并进行外科手术。溶胆石， 1日450?600mg，分 2次服用。
任何疑问，请遵医嘱！
禁用或慎用　

胆道完全阻塞及严重肝功能减退者忌用。由于缺乏怀孕期服用本品的有效率和安全方面的资料，孕妇不宜服用。
给药说明　　

本品需服用较长时期，至少6个月以上，若6个月后超声波检查或胆囊造影无改善者即应停药。
不良反应　

本品的毒性和副作用比鹅去氧胆酸小，一般不引起腹泻(仅 2％)，其他偶见的不良反应有便秘、过敏、瘙痒、头痛、头晕、胃痛、胰腺炎和心动过速等。动物实验未发现 UDCA有致突变作用，光镜和电镜观察未发现肝细胞与熊去氧胆酸一起孵化后有结构上的改变。
主要有腹泻,便秘,过敏反应,胃痛,头痛,头晕,搔痒,心动过缓和胰腺炎.
药物相互作用　

口服避孕药可增加胆汁饱和度，用本品治疗时应采取其他节育措施，以免影响疗效。

包装规格：

·250mg *100 胶囊（UCB Pharma 生产）
·500mg *100 DS 片（Axcan Pharma 生
·150mg *100 片
·250mg *100 片
·300mg *100 片
·500mg *30 缓释片

ACTIGALL (ursodiol) capsule
[Watson Pharma, Inc.]

Prescribing Information

SPECIAL NOTE

Gallbladder stone dissolution with Actigall treatment requires months of therapy. Complete dissolution does not occur in all patients and recurrence of stones within 5 years has been observed in up to 50% of patients who do dissolve their stones on bile acid therapy. Patients should be carefully selected for therapy with ursodiol, and alternative therapies should be considered.

DESCRIPTION

Actigall is a bile acid available as 300 mg capsules suitable for oral administration.

Actigall is ursodiol, USP (ursodeoxycholic acid), a naturally occurring bile acid found in small quantities in normal human bile and in the biles of certain other mammals. It is a bitter-tasting, white powder freely soluble in ethanol, methanol, and glacial acetic acid; sparingly soluble in chloroform; slightly soluble in ether; and insoluble in water. The chemical name for ursodiol is 3α,7β-Dihydroxy-5β-cholan-24-oic acid (C24H40O4). Ursodiol, USP has a molecular weight of 392.57. Its structure is shown below:

Inactive Ingredients: Colloidal silicon dioxide, magnesium stearate, and starch (corn). Gelatin capsules contain ferric oxide, gelatin, and titanium dioxide. The capsules are printed with edible ink containing black iron oxide.

CLINICAL PHARMACOLOGY

About 90% of a therapeutic dose of Actigall is absorbed in the small bowel after oral administration. After absorption, ursodiol enters the portal vein and undergoes efficient extraction from portal blood by the liver (i.e., there is a large “first-pass” effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodiol in bile is concentrated in the gallbladder and expelled into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions provoked by physiologic responses to eating. Only small quantities of ursodiol appear in the systemic circulation and very small amounts are excreted into urine. The sites of the drug’s therapeutic actions are in the liver, bile, and gut lumen.

Beyond conjugation, ursodiol is not altered or catabolized appreciably by the liver or intestinal mucosa. A small proportion of orally administered drug undergoes bacterial degradation with each cycle of enterohepatic circulation. Ursodiol can be both oxidized and reduced at the 7-carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, there is some bacterially catalyzed deconjugation of glyco- and tauro-ursodeoxycholic acid in the small bowel. Free ursodiol, 7-keto-lithocholic acid, and lithocholic acid are relatively insoluble in aqueous media and larger proportions of these compounds are lost from the distal gut into the feces. Reabsorbed free ursodiol is reconjugated by the liver. Eighty percent of lithocholic acid formed in the small bowel is excreted in the feces, but the 20% that is absorbed is sulfated at the 3-hydroxyl group in the liver to relatively insoluble lithocholyl conjugates which are excreted into bile and lost in feces. Absorbed 7-keto-lithocholic acid is stereospecifically reduced in the liver to chenodiol.

Lithocholic acid causes cholestatic liver injury and can cause death from liver failure in certain species unable to form sulfate conjugates. Lithocholic acid is formed by 7-dehydroxylation of the dihydroxy bile acids (ursodiol and chenodiol) in the gut lumen. The 7-dehydroxylation reaction appears to be alpha-specific, i.e., chenodiol is more efficiently 7-dehydroxylated than ursodiol and, for equimolar doses of ursodiol and chenodiol, levels of lithocholic acid appearing in bile are lower with the former. Man has the capacity to sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals, but such a deficiency has not yet been clearly demonstrated.

Pharmacodynamics

Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.

With repeated dosing, bile ursodeoxycholic acid concentrations reach a steady state in about 3 weeks. Although insoluble in aqueous media, cholesterol can be solubilized in at least two different ways in the presence of dihydroxy bile acids. In addition to solubilizing cholesterol in micelles, ursodiol acts by an apparently unique mechanism to cause dispersion of cholesterol as liquid crystals in aqueous media. Thus, even though administration of high doses (e.g., 15-18 mg/kg/day) does not result in a concentration of ursodiol higher than 60% of the total bile acid pool, ursodiol-rich bile effectively solubilizes cholesterol. The overall effect of ursodiol is to increase the concentration level at which saturation of cholesterol occurs.

The various actions of ursodiol combine to change the bile of patients with gallstones from cholesterol-precipitating to cholesterol-solubilizing, thus resulting in bile conducive to cholesterol stone dissolution.

After ursodiol dosing is stopped, the concentration of the bile acid in bile falls exponentially, declining to about 5%-10% of its steady-state level in about 1 week.

Clinical Results

Gallstone Dissolution

On the basis of clinical trial results in a total of 868 patients with radiolucent gallstones treated in 8 studies (three in the U.S. involving 282 patients, one in the U.K. involving 130 patients, and four in Italy involving 456 patients) for periods ranging from 6-78 months with Actigall doses ranging from about 5-20 mg/kg/day, an Actigall dose of about 8-10 mg/kg/day appeared to be the best dose. With an Actigall dose of about 10 mg/kg/day, complete stone dissolution can be anticipated in about 30% of unselected patients with uncalcified gallstones < 20 mm in maximal diameter treated for up to 2 years. Patients with calcified gallstones prior to treatment, or patients who develop stone calcification or gallbladder nonvisualization on treatment, and patients with stones > 20 mm in maximal diameter rarely dissolve their stones. The chance of gallstone dissolution is increased up to 50% in patients with floating or floatable stones (i.e., those with high cholesterol content), and is inversely related to stone size for those < 20 mm in maximal diameter. Complete dissolution was observed in 81% of patients with stones up to 5 mm in diameter. Age, sex, weight, degree of obesity, and serum cholesterol level are not related to the chance of stone dissolution with Actigall.

A nonvisualizing gallbladder by oral cholecystogram prior to the initiation of therapy is not a contraindication to Actigall therapy (the group of patients with nonvisualizing gallbladders in the Actigall studies had complete stone dissolution rates similar to the group of patients with visualizing gallbladders). However, gallbladder nonvisualization developing during ursodiol treatment predicts failure of complete stone dissolution and in such cases therapy should be discontinued.

Partial stone dissolution occurring within 6 months of beginning therapy with Actigall appears to be associated with a > 70% chance of eventual complete stone dissolution with further treatment; partial dissolution observed within 1 year of starting therapy indicates a 40% probability of complete dissolution.

Stone recurrence after dissolution with Actigall therapy was seen within 2 years in 8/27 (30%) of patients in the U.K. studies. Of 16 patients in the U.K. study whose stones had previously dissolved on chenodiol but later recurred, 11 had complete dissolution on Actigall. Stone recurrence has been observed in up to 50% of patients within 5 years of complete stone dissolution on ursodiol therapy. Serial ultrasonographic examinations should be obtained to monitor for recurrence of stones, bearing in mind that radiolucency of the stones should be established before another course of Actigall is instituted. A prophylactic dose of Actigall has not been established.

Gallstone Prevention

Two placebo-controlled, multicenter, double-blind, randomized, parallel group trials in a total of 1,316 obese patients were undertaken to evaluate Actigall in the prevention of gallstone formation in obese patients undergoing rapid weight loss. The first trial consisted of 1,004 obese patients with a body mass index (BMI) ≥ 38 who underwent weight loss induced by means of a very low calorie diet for a period of 16 weeks. An intent-to-treat analysis of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 600, or 1200 mg/day of Actigall experienced a 6%, 3%, and 2% incidence of gallstone formation, respectively. The mean weight loss for this 16-week trial was 47 lb for the placebo group, and 47, 48, and 50 lb for the 300, 600, and 1200 mg/day Actigall groups, respectively.

The second trial consisted of 312 obese patients (BMI ≥ 40) who underwent rapid weight loss through gastric bypass surgery. The trial drug treatment period was for 6 months following this surgery. Results of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 600, or 1200 mg/day of Actigall experienced a 9%, 1%, and 5% incidence of gallstone formation, respectively. The mean weight loss for this 6-month trial was 64 lb for the placebo group, and 67, 74, and 72 lb for the 300, 600, and 1200 mg/day Actigall groups, respectively.

ALTERNATIVE THERAPIES

Watchful Waiting

Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of development of moderate-to-severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7%-27% in 5 years. Presumably the rate is higher for patients already having symptoms.

Cholecystectomy

For patients with symptomatic gallstones, surgery offers the advantage of immediate and permanent stone removal, but carries a high risk in some patients. About 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum of surgical risk varies as a function of age and the presence of disease other than cholelithiasis.

Mortality Rates for Cholecystectomy in the U.S. (National Halothane Study, JAMA 1966; 197:775-8) 27,600 Cholecystectomies (Smoothed Rates) Deaths/1000 Operations***

	Age (Yrs)	Cholecystectomy	Cholecystectomy + Common Duct Exploration
In good health or with moderate systemic disease.
With severe or extreme systemic disease.
Includes both elective and emergency surgery.
Low Risk Patients*
Women	0-49	.54	2.13
	50-69	2.80	10.10
Men	0-49	1.04	4.12
	50-69	5.41	19.23
High Risk Patients**
Women	0-49	12.66	47.62
	50-69	17.24	58.82
Men	0-49	24.39	90.91
	50-69	33.33	111.11

Women in good health or who have only moderate systemic disease and are under 49 years of age have the lowest surgical mortality rate (0.054); men in all categories have a surgical mortality rate twice that of women. Common duct exploration quadruples the rates in all categories. The rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.

INDICATIONS AND USAGE

1. Actigall is indicated for patients with radiolucent, noncalcified gallbladder stones < 20 mm in greatest diameter in whom elective cholecystectomy would be undertaken except for the presence of increased surgical risk due to systemic disease, advanced age, idiosyncratic reaction to general anesthesia, or for those patients who refuse surgery. Safety of use of Actigall beyond 24 months is not established.

2. Actigall is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss

3. CONTRAINDICATIONS

1. Actigall will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Hence, patients with such stones are not candidates for Actigall therapy.

2. Patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-gastrointestinal fistula are not candidates for Actigall therapy.

3. Allergy to bile acids.

4. PRECAUTIONS

5. Liver Tests

Ursodiol therapy has not been associated with liver damage. Lithocholic acid, a naturally occurring bile acid, is known to be a liver-toxic metabolite. This bile acid is formed in the gut from ursodiol less efficiently and in smaller amounts than that seen from chenodiol. Lithocholic acid is detoxified in the liver by sulfation and, although man appears to be an efficient sulfater, it is possible that some patients may have a congenital or acquired deficiency in sulfation, thereby predisposing them to lithocholate-induced liver damage.

Abnormalities in liver enzymes have not been associated with Actigall therapy and, in fact, Actigall has been shown to decrease liver enzyme levels in liver disease. However, patients given Actigall should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances.

Drug Interactions

Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of Actigall by reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids in vitro and may be expected to interfere with Actigall 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 Actigall.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ursodeoxycholic acid was tested in 2-year oral carcinogenicity studies in CD-1 mice and Sprague-Dawley rats at daily doses of 50, 250, and 1000 mg/kg/day. It was not tumorigenic in mice. In the rat study, it produced statistically significant dose-related increased incidences of pheochromocytomas of adrenal medulla in males (p=0.014, Peto trend test) and females (p=0.004, Peto trend test). A 78-week rat study employing intrarectal instillation of lithocholic acid and tauro-deoxycholic acid, metabolites of ursodiol and chenodiol, has been conducted. These bile acids alone did not produce any tumors. A tumor-promoting effect of both metabolites was observed when they were co-administered with a carcinogenic agent. Results of epidemiologic studies suggest that bile acids might be involved in the pathogenesis of human colon cancer in patients who had undergone a cholecystectomy, but direct evidence is lacking. Ursodiol is not mutagenic in the Ames test. Dietary administration of lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits with ursodiol doses up to 200-fold the therapeutic dose and have revealed no evidence of impaired fertility or harm to the fetus at doses of 20- to 100-fold the human dose in rats and at 5-fold the human dose (highest dose tested) in rabbits. Studies employing 100- to 200-fold the human dose in rats have shown some reduction in fertility rate and litter size. There have been no adequate and well-controlled studies of the use of ursodiol in pregnant women, but inadvertent exposure of 4 women to therapeutic doses of the drug in the first trimester of pregnancy during the Actigall trials led to no evidence of effects on the fetus or newborn baby. Although it seems unlikely, the possibility that ursodiol can cause fetal harm cannot be ruled out; hence, the drug is not recommended for use during pregnancy.

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 Actigall is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of Actigall in pediatric patients have not been established.

Geriatric Use

In worldwide clinical studies of Actigall, approximately 14% of subjects were over 65 years of age (approximately 3% were over 75 years old). In a subgroup analysis of existing clinical trials, patients greater than 56 years of age did not exhibit statistically significantly different complete dissolution rates from the younger population. No age-related differences in safety and effectiveness were found. Other reported clinical experience has not identified differences in response in elderly and younger patients. However, small differences in efficacy and greater sensitivity of some elderly individuals taking Actigall cannot be ruled out. Therefore, it is recommended that dosing proceed with caution in this population.

ADVERSE REACTIONS

The nature and frequency of adverse experiences were similar across all groups.

The following tables provide comprehensive listings of the adverse experiences reported that occurred with a 5% incidence level:

GALLSTONE DISSOLUTION
	Ursodiol		Placebo
	8-10 mg/kg/day (N=155)		(N=159)
	N	(%)	N	(%)
Body as a Whole
Allergy	8	(5.2)	7	(4.4)
Chest Pain	5	(3.2)	10	(6.3)
Fatigue	7	(4.5)	8	(5.0)
Infection Viral	30	(19.4)	41	(25.8)
Digestive System
Abdominal Pain	67	(43.2)	70	(44.0)
Cholecystitis	8	(5.2)	7	(4.4)
Constipation	15	(9.7)	14	(8.8)
Diarrhea	42	(27.1)	34	(21.4)
Dyspepsia	26	(16.8)	18	(11.3)
Flatulence	12	(7.7)	12	(7.5)
Gastrointestinal Disorder	6	(3.9)	8	(5.0)
Nausea	22	(14.2)	27	(17.0)
Vomiting	15	(9.7)	11	(6.9)
Musculoskeletal System
Arthralgia	12	(7.7)	24	(15.1)
Arthritis	9	(5.8)	4	(2.5)
Back Pain	11	(7.1)	18	(11.3)
Myalgia	9	(5.8)	9	(5.7)
Nervous System
Headache	28	(18.1)	34	(21.4)
Insomnia	3	(1.9)	8	(5.0)
Respiratory System
Bronchitis	10	(6.5)	6	(3.8)
Coughing	11	(7.1)	7	(4.4)
Pharyngitis	13	(8.4)	5	(3.1)
Rhinitis	8	(5.2)	11	(6.9)
Sinusitis	17	(11.0)	18	(11.3)
Upper Respiratory
Tract Infection	24	(15.5)	21	(13.2)
Urogenital System
Urinary Tract Infection	10	(6.5)	7	(4.4)
GALLSTONE PREVENTION
	Actigall		Placebo
	600 mg (N=322)		(N=325)
	N	(%)	N	(%)
Body as a Whole
Fatigue	25	(7.8)	33	(10.2)
Infection Viral	29	(9.0)	29	(8.9)
Influenza-like Symptoms	21	(6.5)	19	(5.8)
Digestive System
Abdominal Pain	20	(6.2)	39	(12.0)
Constipation	85	(26.4)	72	(22.2)
Diarrhea	81	(25.2)	68	(20.9)
Flatulence	15	(4.7)	24	(7.4)
Nausea	56	(17.4)	43	(13.2)
Vomiting	44	(13.7)	44	(13.5)
Musculoskeletal System
Back Pain	38	(11.8)	21	(6.5)
Musculoskeletal Pain	19	(5.9)	15	(4.6)
Nervous System
Dizziness	53	(16.5)	42	(12.9)
Headache	80	(24.8)	78	(24.0)
Respiratory System
Pharyngitis	10	(3.1)	19	(5.8)
Sinusitis	17	(5.3)	18	(5.5)
Upper Respiratory
Tract Infection	40	(12.4)	35	(10.8)
Skin and Appendages
Alopecia	17	(5.3)	8	(2.5)
Urogenital System
Dysmenorrhea	18	(5.6)	19	(5.8)

OVERDOSAGE

Neither accidental nor intentional overdosing with Actigall has been reported. Doses of Actigall in the range of 16-20 mg/kg/day have been tolerated for 6-37 months without symptoms by 7 patients. The LD50 for ursodiol in rats is over 5000 mg/kg given over 7-10 days and over 7500 mg/kg for mice. The most likely manifestation of severe overdose with Actigall would probably be diarrhea, which should be treated symptomatically.

DOSAGE AND ADMINISTRATION

Gallstone Dissolution

The recommended dose for Actigall treatment of radiolucent gallbladder stones is 8-10 mg/kg/day given in 2 or 3 divided doses.

Ultrasound images of the gallbladder should be obtained at 6-month intervals for the first year of Actigall therapy to monitor gallstone response. If gallstones appear to have dissolved, Actigall therapy should be continued and dissolution confirmed on a repeat ultrasound examination within 1-3 months. Most patients who eventually achieve complete stone dissolution will show partial or complete dissolution at the first on-treatment reevaluation. If partial stone dissolution is not seen by 12 months of Actigall therapy, the likelihood of success is greatly reduced.

Gallstone Prevention

The recommended dosage of Actigall for gallstone prevention in patients undergoing rapid weight loss is 600 mg/day (300 mg b.i.d.).

HOW SUPPLIED

Actigall Capsules are opaque white and pink capsules imprinted “ACTIGALL” on one half and “300 mg” on the other half of the capsule in black.

Bottles of 100 are supplied with child-resistant closures.
(NDC 52544-930-01)

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).