URSODIOL

Ursodiol Capsules, USP are a bile acid available as 300 mg capsules suitable for oral administration. Ursodiol, USP (ursodeoxycholic acid), is a naturally occurring bile acid found in small quantities in normal human bile and in the biles of certain other mammals. It is a white or almost white crystalline powder, slightly soluble in water, freely soluble in alcohol, slightly soluble in acetone and methylene chloride. The chemical name for ursodiol is 3α,7β-Dihydroxy-5β-cholan-24-oic acid (C 24 H 40 O 4 ). Ursodiol, USP has a molecular weight of 392.57 g/mol. Its structure is shown below: Each capsule contains Ursodiol USP, 300 mg and the following Inactive Ingredients: Maize Starch B, colloidal silicon dioxide and magnesium stearate. Additionally, the hard gelatin capsule shell contains: FD&C Red 40, Titanium Dioxide, D&C Yellow 10, gelatin and water. Each capsule is imprinted with black pharmaceutical ink which contains shellac, black iron oxide and potassium hydroxide. chemicalstructure

Ursodiol capsules are 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 capsules beyond 24 months is not established. Ursodiol capsules are indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.

Gallstone Dissolution The recommended dose for ursodiol capsules 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 ursodiol capsules therapy to monitor gallstone response. If gallstones appear to have dissolved, ursodiol capsules therapy should be continued and dissolution confirmed on a repeat ultrasound examination within 1 to 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 ursodiol capsules therapy, the likelihood of success is greatly reduced. Gallstone Prevention The recommended dosage of ursodiol capsules for gallstone prevention in patients undergoing rapid weight loss is 600 mg/day (300 mg b.i.d.).

Ursodiol capsules will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Hence, patients with such stones are not candidates for ursodiol capsules therapy. Patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-gastrointestinal fistula are not candidates for ursodiol capsules therapy. Allergy to bile acids.

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 Capsules 8 - 10 mg/kg/day (N = 155) Placebo (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 Ursodiol Capsules 600 mg (N = 322) Placebo (N = 325) N (%) N (%) Body as a Whole Fatigue Infection Viral Influenza-like Symptoms 25 29 21 (7.8) (9.0) (6.5) 33 29 19 (10.2) (8.9) (5.8) Digestive System Abdominal Pain Constipation Diarrhea Flatulence Nausea Vomiting 20 85 81 15 56 44 (6.2) (26.4) (25.2) (4.7) (17.4) (13.7) 39 72 68 24 43 44 (12.0) (22.2) (20.9) (7.4) (13.2) (13.5) Musculoskeletal System Back Pain Musculoskeletal Pain 38 19 (11.8) (5.9) 21 15 (6.5) (4.6) Nervous System Dizziness Headache 53 80 (16.5) (24.8) 42 78 (12.9) (24.0) Respiratory System Pharyngitis Sinusitis Upper Respiratory Tract Infection 10 17 40 (3.1) (5.3) (12.4) 19 18 35 (5.8) (5.5) (10.8) Skin and Appendages Alopecia 17 (5.3) 8 (2.5) Urogenital System Dysmenorrhea 18 (5.6) 19 (5.8)

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