URSODIOL: 3,624 Adverse Event Reports & Safety Profile

Ursodiol tablets, USP 250 mg is available as a film-coated tablet for oral administration. Ursodiol tablets, USP 500 mg is available as a scored film-coated tablet for oral administration. Ursodiol (ursodeoxycholic acid, UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water. The chemical name of ursodiol is 3α,7ß-dihydroxy-5ß-cholan-24-oic (C 24 H 40 O 4 ). Ursodiol has a molecular weight of 392.56. Its structure is shown below. Inactive ingredients: microcrystalline cellulose, povidone, sodium starch glycolate, magnesium stearate, ethylcellulose, dibutyl sebacate, carnauba wax, hydroxypropyl methylcellulose, PEG 3350, PEG 8000, cetyl alcohol, sodium lauryl sulfate and hydrogen peroxide. The structure is shown below, Ursodiol (ursodeoxycholic acid, UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water. The chemical name of ursodiol is 3α,7ß-dihydroxy-5ß-cholan-24-oic (C24H40O4). Ursodiol has a molecular weight of 392.56.

INDICATIONS & USAGE 1. Ursodiol capsules, USP 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.

DOSAGE AND ADMINISTRATION Gallstone Dissolution The recommended dose for ursodiol 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 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.

Gallstone Dissolution

The recommended dose for ursodiol 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 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.

CONTRAINDICATIONS 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.

REACTIONS Most common adverse reactions reported with the use of ursodiol during worldwide postmarketing and clinical experience (≥1%) are, in alphabetical order: abdominal discomfort, abdominal pain, alopecia, diarrhea, nausea, pruritus, and rash ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following table summarizes the adverse reactions observed in two placebo-controlled clinical trials. ADVERSE REACTIONS VISIT AT 12 MONTHS VISIT AT 24 MONTHS UDCA n (%) Placebo n (%) UDCA n (%) Placebo n (%) Diarrhea --- --- 1 (1.32) --- Elevated creatinine --- --- 1 (1.32) --- Elevated blood glucose 1 (1.18) --- 1 (1.32) --- Leukopenia --- --- 2 (2.63) --- Peptic ulcer --- --- 1 (1.32) --- Skin rash --- --- 2 (2.63) --- Thrombocytopenia --- --- 1 (1.32) --- Note: Those adverse reactions occurring at the same or higher incidence in the placebo as in the UDCA group have been deleted from this table (this includes diarrhea and thrombocytopenia at 12 months, nausea/vomiting, fever and other toxicity). UDCA = Ursodeoxycholic acid = Ursodiol In a randomized, cross-over study in sixty PBC patients, seven patients (11.6%) reported nine adverse reactions: abdominal pain and asthenia (1 patient), nausea (3 patients), dyspepsia (2 patients) and anorexia and esophagitis (1 patient each). One patient on the twice a day regimen (total dose 1,000 mg) withdrew due to nausea. All of these nine adverse reactions except esophagitis were observed with the twice a day regimen at a total daily dose of 1,000 mg or greater. However, an adverse reaction may occur at any dose.

6.2 Postmarketing Experience The following adverse reactions, presented by system organ class in alphabetical order, have been identified during postapproval 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: abdominal discomfort, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting. General disorders and administration site conditions: malaise, peripheral edema, pyrexia. Hepatobiliary disorders: jaundice (or aggravation of preexisting jaundice).

Immune System

Disorders: Drug hypersensitivity to include facial edema, urticaria, angioedema and laryngeal edema.

Abnormal Laboratory

Tests: ALT increased, AST increased, blood alkaline phosphatase increased, blood bilirubin increased, y-GT increased, hepatic enzyme increased, liver function test abnormal, transaminases increased. Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: dizziness, headache. Respiratory, thoracic and mediastinal disorders: cough. Skin and subcutaneous tissue disorder: alopecia, pruritus, rash. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch.

AND PRECAUTIONS

• Abnormal Liver Function Tests : Liver function tests (γ-GT, alkaline phosphatase, AST, ALT) and bilirubin level should be monitored. Treatment discontinuation should be considered if parameters increase to a level considered clinically significant in patients with stable historical liver function test levels. Caution should be exercised to maintain patients’ bile flow. (5.1)
• Enteroliths in Patients with Risk for Intestinal Stenosis or Stasis: Monitor for obstructive gastrointestinal symptoms; if symptoms occur, hold ursodiol until a clinical evaluation has been conducted. ( 5.2 )

5.1 Abnormal Liver Function Tests Liver function tests ( y -GT, alkaline phosphatase, AST, ALT) and bilirubin levels should be monitored every month for three months after start of therapy, and every six months thereafter. This monitoring will allow the early detection of a possible deterioration of the hepatic function. Treatment discontinuation should be considered if the above parameters increase to a level considered clinically significant in patients with stable historical liver function test levels. Caution has to be exercised to maintain the bile flow of the patients taking ursodiol.

5.2 Enteroliths in Patients with Risk for Intestinal Stenosis or Stasis There have been rare postmarketing reports of Ursodiol tablets-treated patients who developed enteroliths (bezoars) resulting in obstructive symptoms that required surgical intervention. These patients had medical conditions that predisposed them to intestinal stenosis or stasis (e.g., surgical enteroanastomoses, Crohn&apos;s disease). If a patient presents with obstructive gastrointestinal symptoms, hold Ursodiol tablets until a clinical evaluation has been conducted.

PRECAUTIONS 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 ursodiol capsules therapy and, in fact, ursodiol capsules has been shown to decrease liver enzyme levels in liver disease. However, patients given ursodiol capsules 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 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. 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 1,000 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

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 capsules 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 capsules is administered to a nursing mother.

Pediatric Use

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

Geriatric

Use In worldwide clinical studies of ursodiol capsules, 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 ursodiol capsules cannot be ruled out. Therefore, it is recommended that dosing proceed with caution in this population.

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 ursodiol capsules therapy and, in fact, ursodiol capsules has been shown to decrease liver enzyme levels in liver disease. However, patients given ursodiol capsules 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 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. 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 1,000 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 coadministered 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.