URSODIOL

Ursodiol is 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, freely soluble in alcohol and glacial acetic acid; slightly soluble in chloroform and ether; and practically insoluble in water. 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 392.6 g/mol. Its structure is shown below: Inactive Ingredients: Hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, povidone, silicon dioxide and sodium starch glycolate type A. Capsule contains gelatin, FD & C Blue 1, FD & C Red 3 and titanium dioxide. The capsule is printed with black pharmaceutical ink which contains black iron oxide, potassium hydroxide and shellac. FDA approved dissolution method differ from the USP. Image

1. 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. 2. Ursodiol capsules are indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.

Gallstone Dissolution The recommended dose for ursodiol treatment of radiolucent gallbladder stones is 8 mg/kg/day to 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 therapy to monitor gallstone response. If gallstones appear to have dissolved, ursodiol 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 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.).

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.

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 mg/kg/day to 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) 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 600 mg (N = 322) Placebo (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) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Postmarketing Experience The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post-approval use of ursodiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders : enteroliths (bezoars).

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 adsorb 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.