Reltone Drug Information

1. Reltone™ 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 Reltone™ beyond 24 months is not established. 2. Reltone™ is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.

Gallstone Dissolution The recommended dose for Reltone™ 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 Reltone™ therapy to monitor gallstone response. If gallstones appear to have dissolved, Reltone™ 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 Reltone™ therapy, the likelihood of success is greatly reduced. Gallstone Prevention The recommended dosage of Reltone™ for gallstone prevention in patients undergoing rapid weight loss is 600 mg/day.

To report SUSPECTED ADVERSE REACTIONS, contact Intra-Sana Laboratories at 1-702-980-8963 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 7 Chest Pain 5 10 Fatigue 7 8 Infection Viral 30 41 Digestive System Abdominal Pain 67 70 Cholecystitis 8 7 Constipation 15 14 Diarrhea 42 34 Dyspepsia 26 18 Flatulence 12 12 Gastrointestinal Disorder 6 8 Nausea 22 27 Vomiting 15 11 Musculoskeletal System Arthralgia 12 24 Arthritis 9 4 Back Pain 11 18 Myalgia 9 9 Nervous System Headache 28 34 Insomnia 3 8 Respiratory System Bronchitis 10 6 Coughing 11 7 Pharyngitis 13 5 Rhinitis 8 11 Sinusitis 17 18 Upper Respiratory Tract Infection 24 21 Urogenital System Urinary Tract Infection 10 7 GALLSTONE PREVENTION Ursodiol Placebo 600 mg (N=322) (N=325) N (%) N (%) Body as a Whole Fatigue 25 33 Infection Viral 29 29 Influenza-like Symptoms 21 19 Digestive System Abdominal Pain 20 39 Constipation 85 72 Diarrhea 81 68 Flatulence 15 24 Nausea 56 43 Vomiting 44 44 Musculoskeletal System Back Pain 38 21 Musculoskeletal Pain 19 15 Nervous System Dizziness 53 42 Headache 80 78 Respiratory System Pharyngitis 10 19 Sinusitis 17 18 Upper Respiratory Tract Infection 40 35 Skin and Appendages Alopecia 17 8 Urogenital System Dysmenorrhea 18 19

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 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.

Pregnancy 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 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.

Pediatric Use The safety and effectiveness of ursodiol in pediatric patients have not been established.

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

Neither accidental nor intentional overdosing with ursodiol has been reported. Doses of ursodiol in the range of 16-20 mg/kg/day have been tolerated for 6 to 37 months without symptoms by 7 patients. The LD 50 for ursodiol in rats is over 5000 mg/kg given over 7 to 10 days and over 7500 mg/kg for mice.

The most likely manifestation of severe overdose with ursodiol would probably be diarrhea, which should be treated symptomatically.