ADVERSE REACTIONS SECTION.

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 5% incidence level:Figure Gallstone Dissolution In Ursodiol and Placebo PatientsGALLSTONE DISSOLUTIONUrsodiol8 10 mg/kg/day(N=155)Placebo(N=159)N(%)N(%)Body as Whole Allergy8(5.2)7(4.4) Chest Pain5(3.2)10(6.3) Fatigue7(4.5)8(5.0) Infection Viral30(19.4)41(25.8)Digestive System Abdominal Pain67(43.2)70(44.0) Cholecystitis8(5.2)7(4.4) Constipation15 (9.7)14 (8.8) Diarrhea42 (27.1)34 (21.4) Dyspepsia26(16.8)18(11.3) Flatulence12 (7.7)12 (7.5) Gastrointestinal Disorder6 (3.9)8 (5.0) Nausea22 (14.2)27 (17.0) Vomiting15 (9.7)11 (6.9)Musculoskeletal System Arthralgia12 (7.7)24 (15.1) Arthritis9 (5.8)4 (2.5) Back Pain11 (7.1)18 (11.3) Myalgia9 (5.8)9 (5.7)Nervous System Headache28 (18.1)34 (21.4) Insomnia3 (1.9)8 (5.0)Respiratory System Bronchitis10 (6.5)6 (3.8) Coughing11 (7.1)7 (4.4) Pharyngitis13 (8.4)5 (3.1) Rhinitis8 (5.2)11 (6.9) Sinusitis17 (11.0)18 (11.3) Upper Respiratory Tract Infection24 (15.5)21 (13.2)Urogenital System Urinary Tract Infection10 (6.5)7 (4.4)Figure Gallstone Prevention in Ursodiol and Placebo-Treated PatientsGALLSTONE PREVENTIONUrsodiol600 mg(N=322)Placebo(N=325)N(%)N(%)Body as Whole Fatigue25 (7.8)33 (10.2) Infection Viral29 (9.0)29 (8.9) Influenza-like Symptoms21 (6.5)19 (5.8)Digestive System Abdominal Pain20 (6.2)39 (12.0) Constipation85 (26.4)72 (22.2) Diarrhea81 (25.2)68 (20.9) Flatulence15 (4.7)24 (7.4) Nausea56 (17.4)43 (13.2) Vomiting 44 (13.7)44 (13.5)Musculoskeletal System Back Pain38 (11.8)21 (6.5) Musculoskeletal Pain19 (5.9)15 (4.6)Nervous System Dizziness 53 (16.5)42 (12.9) Headache80 (24.8)78 (24.0)Respiratory System Pharyngitis10 (3.1)19 (5.8) Sinusitis17(5.3)18(5.5) Upper Respiratory Tract Infection40 (12.4)35 (10.8)Skin and Appendages Alopecia17 (5.3)8 (2.5)Urogenital System Dysmenorrhea18 (5.6)19 (5.8).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. About 90% of therapeutic dose of ursodiol 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 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 drugs 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. 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, reduced capacity to sulfate may exist in some individuals, but such deficiency has not yet been clearly demonstrated.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. 1.Ursodiol will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Hence, patients with such stones are not candidates for ursodiol 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 ursodiol therapy.3.Allergy to bile acids.. 1.Ursodiol will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Hence, patients with such stones are not candidates for ursodiol 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 ursodiol therapy.. 3.Allergy to bile acids.

DESCRIPTION SECTION.

DESCRIPTION. Ursodiol is bile acid available as 300 mg capsules suitable for oral administration.Ursodiol, USP (ursodeoxycholic acid), is naturally occurring bile acid found in small quantities in normal human bile and in the biles of certain other mammals. It is 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 3, 7-Dihydroxy-5-cholan-24-oic acid (C24H40O4). Ursodiol, USP has molecular weight of 392.57. Its structure is shown below:Inactive Ingredients: Corn starch, magnesium stearate, silicon dioxide and the capsule shell contain the following ingredients, gelatin, titanium dioxide, D&C Red 28, FD&C Blue and FD&C Red 40.The imprinting ink contains the following: black iron oxide, D&C Yellow 10 Aluminum Lake, FD&C Blue Aluminum Lake, FD&C Blue Aluminum Lake, FD&C Red 40 Aluminum Lake, propylene glycol and shellac glaze.. structural-formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Gallstone Dissolution. The recommended dose for ursodiol treatment of radiolucent gallbladder stones is - 10 mg/kg/day given in or divided doses. Ultrasound images of the gallbladder should be obtained at 6-month intervals for the first year of ursodiol therapy to monitor gallstone response. If gallstones appear to have dissolved, ursodiol therapy should be continued and dissolution confirmed on repeat ultrasound examination within to 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 ursodiol therapy, the likelihood of success is greatly reduced.. Gallstone Prevention. The recommended dosage of ursodiol for gallstone prevention in patients undergoing rapid weight loss is 600 mg/day (300 mg b.i.d.).

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. 1.Ursodiol 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 ursodiol beyond 24 months is not established.2.Ursodiol is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.. 1.Ursodiol 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 ursodiol beyond 24 months is not established.. 2.Ursodiol is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.

PHARMACODYNAMICS SECTION.

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 steady state in about 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 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 cholesterolsolubilizing, 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 week.

PRECAUTIONS SECTION.

PRECAUTIONS. Liver Tests. Ursodiol therapy has not been associated with liver damage. Lithocholic acid, naturally occurring bile acid, is known to be 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 congenital or acquired deficiency in sulfation, thereby predisposing them to lithocholate-induced liver damage.Abnormalities in liver enzymes have not been associated with ursodiol therapy and, in fact, ursodiol has been shown to decrease liver enzyme levels in liver disease. However, patients given ursodiol 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 ursodiol by reducing its absorption. Aluminum-based antacids have been shown to absorb bile acids in vitro and may be expected to interfere with ursodiol 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 ursodiol.. 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). 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. tumor-promoting effect of both metabolites was observed when they were co-administered with 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 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 women to therapeutic doses of the drug in the first trimester of pregnancy during the ursodiol 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 ursodiol is administered to nursing mother.. Pediatric Use. The safety and effectiveness of ursodiol in pediatric patients have not been established.. Geriatric Use. In worldwide clinical studies of ursodiol, approximately 14% of subjects were over 65 years of age (approximately 3% were over 75 years old). In 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 ursodiol cannot be ruled out. Therefore, it is recommended that dosing proceed with caution in this population.