Ursodiol

RECENT MAJOR CHANGES Warnings and Precautions ( 5.2 ) 1/2023

1 INDICATIONS AND USAGE Ursodiol tablets , 250 mg and 500 mg are indicated for the treatment of patients with primary biliary cholangitis (PBC). Ursodiol tablets, 250 mg and 500 mg are bile acids indicated for the treatment of patients with primary biliary cholangitis. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended adult dosage: 13 to15 mg/kg/day administered in two to four divided doses with food. ( 2.1 ) Scored ursodiol tablet USP, 500 mg: scored tablet can be broken in halves to provide recommended dosage. ( 2.3 , 16 ) 2.1 General Dosing Information The recommended adult dosage for ursodiol tablets USP, 250 mg and 500 mg in the treatment of PBC is 13 to15 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 (γ-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 the 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 )].

3 DOSAGE FORMS AND STRENGTHS • Ursodiol Tablets, USP 250 mg: 250 mg tablet • Ursodiol Tablets, USP 500 mg: 500 mg scored tablet • Ursodiol Tablets, USP 250 mg: 250 mg tablet ( 3 ) • Ursodiol Tablets, USP 500 mg: 500 mg scored tablet ( 3 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE 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 Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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.

7 DRUG INTERACTIONS • Bile Acid Sequestering Agents: May interfere with the action of ursodiol tablets, 250 mg and 500 mg by reducing its absorption. ( 7.1 ) • Aluminum-based Antacids: May interfere with the action of ursodiol tablets, 250 mg and 500 mg by reducing its absorption. ( 7.2 ) • Drugs that alter the metabolism of lipids or induce cholestasis may interfere with the action of ursodiol tablets, 250 mg and 500 mg. ( 7.3 ) 7.1 Bile Acid Sequestering Agents Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol tablets, 250 mg and 500 mg 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 tablets, 250 mg and 500 mg 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 tablets, 250 mg and 500 mg.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available published data on the use of ursodiol in pregnant women derived from randomized controlled trials, observational studies, and case series collected over several decades have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Most of the reported exposures to ursodiol occurred in the second and third trimester of pregnancy. In animal reproduction studies, ursodiol had no adverse effects on embryo-fetal development when administered at doses greater than human therapeutic doses (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data No adverse effects on embryo-fetal development were observed with oral administration of ursodiol to pregnant rats and rabbits during organogenesis at doses up to 22 and 7 times, respectively, the maximum recommended human dose (based on body surface area). 8.2 Lactation Risk Summary Ursodiol is naturally present in human milk. There are no reports of adverse effects of ursodiol on the breastfed child, but the reports are extremely limited. There are no data on the effects of ursodiol on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ursodiol tablets, 250 mg and 500 mg and any potential adverse effects on the breastfed child from ursodiol tablets, 250 mg and 500 mg or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ursodiol tablets, 250 mg and 500 mg in pediatric patients have not been established.

12.1 Mechanism of Action Ursodiol, a naturally occurring hydrophilic bile acid, derived from cholesterol, is present as a minor fraction of the total human bile acid pool. Oral administration of ursodiol increases this fraction in a dose related manner, to become the major biliary acid, replacing/displacing toxic concentrations of endogenous hydrophobic bile acids that tend to accumulate in cholestatic liver disease. In addition to the replacement and displacement of toxic bile acids, other mechanisms of action include cytoprotection of the injured bile duct epithelial cells (cholangiocytes) against toxic effects of bile acids, inhibition of apoptosis of hepatocytes, immunomodulatory effects, and stimulation of bile secretion by hepatocytes and cholangiocytes.

11 DESCRIPTION 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: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, polyethylene glycol, sodium lauryl sulfate, sodium starch glycolate. The inert ingredients in film coating material are: hypromellose, polyethylene glycol, titanium dioxide. Structural Formula

10 OVERDOSAGE There have been no reports of accidental or intentional overdosage with ursodiol. Single oral doses of ursodiol at 10 g/kg in mice and dogs, and 5 g/kg in rats were not lethal. A single oral dose of ursodiol at 1.5 g/kg was lethal in hamsters. Symptoms of acute toxicity were salivation and vomiting in dogs, and ataxia, dyspnea, ptosis, agonal convulsions and coma in hamsters.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Ursodiol Tablets, USP 250 mg Each Ursodiol Tablet, USP 250 mg is a white to off-white, oval shaped, film-coated tablet debossed with “G72” on one side and “250” on the other side and contains 250 mg ursodiol, USP. Ursodiol Tablets, USP 250 mg are available in: Bottles of 30 tablets, NDC 68462-473-30 Bottles of 100 tablets, NDC 68462-473-01 Bottles of 500 tablets, NDC 68462-473-05 16.2 Ursodiol Tablets, USP 500 mg Each Ursodiol Tablet, USP 500 mg is a white to off-white, oval shaped, film-coated tablet debossed with “U 11” on one side and a score line on the other side and contains 500 mg ursodiol, USP. Ursodiol Tablets, USP 500 mg are available in: Bottles of 30 tablets, NDC 68462-474-30 Bottles of 100 tablets, NDC 68462-474-01 Bottles of 500 tablets, NDC 68462-474-05 Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight container. Half-tablets (scored Ursodiol Tablets, USP 500 mg broken in half) maintain acceptable quality for up to 28 days when stored in the current packaging (bottles) at 20°C to 25°C (68°F to 77°F). Due to the bitter taste, the halved segments should be stored separately from the whole tablets [see Dosage and Administration ( 2.3 )].