URSODIOL

Ursodiol Tablets, USP 250 mg are available as a film-coated tablet for oral administration. Ursodiol Tablets, USP 500 mg are available as a scored film-coated tablet for oral administration. Ursodiol, USP (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 white or almost white crystalline powder freely soluble in ethanol, slightly soluble in acetone, and practically insoluble in Methylene chloride and water. The chemical name of ursodiol, USP is 3α,7ß-dihydroxy-5ß-cholan-24-oic acid (C 24 H 40 O 4 ). Ursodiol, USP has a molecular weight of 392.6. Its structure is shown below. Inactive ingredients: caprylic/capric triglycerides, copovidone, hypromellose, microcrystalline cellulose, magnesium stearate, povidone, polydextrose, polyethylene glycol 3350, sodium starch glycolate type A and titanium dioxide. ursodiol-structure.jpg

Ursodiol tablets are indicated for the treatment of patients with primary biliary cholangitis (PBC). Ursodiol tablets are bile acids indicated for the treatment of patients with primary biliary cholangitis. ( 1 )

• Recommended adult dosage: 13 to 15 mg/kg/day administered in two to four divided doses with food. ( 2.1 ) • Scored ursodiol 500 mg tablet: scored tablet can be broken in halves to provide recommended dosage. ( 2.3 , 16.2 ) 2.1 General Dosing Information The recommended adult dosage for ursodiol tablets in the treatment of PBC is 13 to 15 mg/kg/day administered in two to four divided doses with food. Dosing regimen should be adjusted according to each patient’s need at the discretion of the physician. 2.2 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 [see Warnings and Precautions ( 5.1 ) ]. 2.3 Scoring the Ursodiol Tablet 500 mg The ursodiol 500 mg scored tablet can be broken in halves to provide recommended dosage. To break ursodiol 500 mg scored tablet easily, place the tablet on a flat surface with the scored section on top. Hold the tablet with your thumbs placed close to the scored part of the tablet (groove). Then apply gentle pressure and snap the tablet segments apart (segments breaking incorrectly should not be used). The segments should be washed down unchewed, with water, keeping the segments in the mouth can reveal a bitter taste. Due to the bitter taste, segments should be stored separately from whole tablets. [see How Supplied/Storage and Handling (16.2) ] .

Patients with complete biliary obstruction and known hypersensitivity or intolerance to ursodiol or any of the components of the formulation. Patients with complete biliary obstruction and known hypersensitivity or intolerance to ursodiol or any of the components of the formulation. ( 4 )

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 Endo at 1-800-828-9393 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 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: abdominal discomfort, abdominal pain, enteroliths (bezoars), constipation, diarrhea, dyspepsia, nausea, vomiting. • General disorders and administration site conditions: malaise, peripheral edema, pyrexia. • Hepatobiliary disorders: jaundice (or aggravation of pre-existing 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, γ-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.

• Bile Acid Sequestering Agents : May interfere with the action of ursodiol by reducing its absorption. ( 7.1 ) • Aluminum-based Antacids : May interfere with the action of ursodiol by reducing its absorption. ( 7.2 ) • Drugs that alter the metabolism of lipids or induce cholestasis may interfere with the action of ursodiol. ( 7.3 ) 7.1 Bile Acid Sequestering Agents Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption. 7.2 Aluminum-based Antacids 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. 7.3 Drugs Affecting Lipid Metabolism 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.