HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Ursodiol ablet s, USP 250 mg Each ursodiol tablets, USP 250 mg elliptical, biconvex, film-coated tablet, white, engraved with URS785, contains 250 mg of ursodiol. Available in bottles of 100 tablets (NDC 0591-2998-01). 16.2 Ursodiol tablets, SP 500 mg Each ursodiol tablets, USP 500 mg elliptical, biconvex, scored, film-coated tablet, white, engraved with URS790, contains 500 mg of ursodiol. Available in bottles of 100 tablets (NDC 0591-3005-01). Store at 20C to 25C (68F to 77F). Dispense in 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 20oC to 25oC (68oF to 77oF). Due to the bitter taste, the halved segments should be stored separately from the whole tablets [see Dosage and Administration (2.3) ].

ADVERSE REACTIONS SECTION.

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 Actavis at 1-800-272-5525 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 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 REACTIONSVISIT AT 12 MONTHSVISIT AT 24 MONTHS UDCAn (%)Placebon (%)UDCAn (%)Placebon (%)Diarrhea ------1 (1.32)---Elevated creatinine ------1 (1.32)---Elevated blood glucose (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 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 day regimen (total dose 1000 mg) withdrew due to nausea. All of these nine adverse reactions except esophagitis were observed with the twice day regimen at total daily dose of 1000 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 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, -GT increased, hepatic enzyme increased, liver function test abnormal, transaminases increased. Musculoskeletal and connective tissue disorders: myalgiaNervous system disorders: dizziness, headache.Respiratory, thoracic and mediastinal disorders: cough.Skin and subcutaneous tissue disorder: alopecia, pruritus, rash.. 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 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, -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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis Mutagen esis Impairment of Fertility In two 24-month oral carcinogenicity studies in mice, ursodiol at doses up to 1,000 mg/kg/day (3,000 mg/m2/day) was not tumorigenic. Based on body surface area, for 50 kg person of average height (1.46 m2 body surface area), this dose represents 5.4 times the recommended maximum clinical dose of 15 mg/kg/day (555 mg/m2/day). In two-year oral carcinogenicity study in Fischer 344 rats, ursodiol at doses up to 300 mg/kg/day (1,800 mg/m2/day, 3.2 times the recommended maximum human dose based on body surface area) was not tumorigenic. In life-span (126-138 weeks) oral carcinogenicity study, Sprague-Dawley rats were treated with doses of 33 to 300 mg/kg/day, 0.4 to 3.2 times the recommended maximum human dose based on body surface area. Ursodiol produced significantly (p<0.5, Fishers exact test) increased incidence of pheochromocytomas of the adrenal medulla in females of the highest dose group. In 103-week oral carcinogenicity studies of lithocholic acid, metabolite of ursodiol, doses up to 250 mg/kg/day in mice and 500 mg/kg/day in rats did not produce any tumors. In 78-week rat study, intrarectal instillation of lithocholic acid (1 mg/kg/day) for 13 months did not produce colorectal tumors. tumor-promoting effect was observed when it was administered after single intrarectal dose of known carcinogen N-methyl-N-nitro-N-nitrosoguanidine. On the other hand, in 32-week rat study, ursodiol at daily dose of 240 mg/kg (1,440 mg/m2, 2.6 times the maximum recommended human dose based on body surface area) suppressed the colonic carcinogenic effect of another known carcinogen azoxymethane. Ursodiol was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test, the human lymphocyte sister chromatid exchange test, the mouse spermatogonia chromosome aberration test, the Chinese hamster micronucleus test and the Chinese hamster bone marrow cell chromosome aberration test. Ursodiol at oral doses of up to 2,700 mg/kg/day (16,200 mg/m2/day, 29 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ursodiol, naturally occurring hydrophilic bile acid, derived from cholesterol, is present as minor fraction of the total human bile acid pool. Oral administration of ursodiol increases this fraction in 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.. 12.2 Pharmacodynamics Lithocholic acid, when administered chronically to animals, causes cholestatic liver injury that may lead to death from liver failure in certain species unable to form sulfate conjugates. Ursodiol is 7-dehydroxylated more slowly than chenodiol. For equimolar doses of ursodiol and chenodiol, steady state levels of lithocholic acid in biliary bile acids are lower during ursodiol administration than with chenodiol administration. Humans and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, reduced capacity to sulfate may exist in some individuals. 12.3 Pharmacokinetics Ursodiol (UDCA) is normally present as minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of ursodiol is absorbed by passive diffusion and its absorption is incomplete. Once absorbed, ursodiol undergoes hepatic extraction to the extent of about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, ursodiol is conjugated with glycine or taurine, then secreted into bile. These conjugates of ursodiol are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some ursodiol is epimerized to chenodiol (CDCA) via 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. In healthy subjects, at least 70% of ursodiol (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated ursodiol to plasma protein in healthy subjects or PBC patients. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1% except in severe cholestatic liver disease. During chronic administration of ursodiol, it becomes major biliary and plasma bile acid. At chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.

CLINICAL STUDIES SECTION.

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 REACTIONSVISIT AT 12 MONTHSVISIT AT 24 MONTHS UDCAn (%)Placebon (%)UDCAn (%)Placebon (%)Diarrhea ------1 (1.32)---Elevated creatinine ------1 (1.32)---Elevated blood glucose (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 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 day regimen (total dose 1000 mg) withdrew due to nausea. All of these nine adverse reactions except esophagitis were observed with the twice day regimen at total daily dose of 1000 mg or greater. However, an adverse reaction may occur at any dose.

DESCRIPTION SECTION.

11 DESCRIPTION Ursodiol tablets, USP 250 mg is available as film-coated tablet for oral administration. Ursodiol tablets, USP 500 mg is available as scored film-coated tablet for oral administration. Ursodiol (ursodeoxycholic acid, UDCA) is 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 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 3,7ss-dihydroxy-5ss-cholan-24-oic (C24H40O4). Ursodiol has 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 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 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 3,7ss-dihydroxy-5ss-cholan-24-oic (C24H40O4). Ursodiol has molecular weight of 392.56.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Recommended adult dosage: 13-15 mg/kg/day administered in two to four divided doses with food (2.1) Scored ursodiol tablets, USP 500 mg: scored tablet can be broken in halves to provide recommended dosage (2.3, 16.2) Recommended adult dosage: 13-15 mg/kg/day administered in two to four divided doses with food (2.1) Scored ursodiol tablets, USP 500 mg: 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, USP 250 and 500 mg in the treatment of PBC is 13-15 mg/kg/day administered in two to four divided doses with food. Dosing regimen should be adjusted according to each patients need at the discretion of the physician. 2.2 Liver Function Tests Liver function tests (-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 s, USP 500 mg The ursodiol tablets, USP 500 mg scored tablet can be broken in halves to provide recommended dosage. To break ursodiol tablets, USP 500 mg scored tablet easily, place the tablet on 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 bitter taste. Due to the bitter taste, segments should be stored separately from whole tablets. [see How Supplied/Storage and Handling (16.2) ].

DRUG INTERACTIONS SECTION.

7 Drug Interactions Bile Acid Sequestering Agents: May interfere with the action of ursodiol tablets, USP 250 mg and 500 mg by reducing its absorption (7.1) Aluminum-based Antacids: May interfere with the action of ursodiol tablets, USP 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, USP 250 mg and 500 mg (7.3). Bile Acid Sequestering Agents: May interfere with the action of ursodiol tablets, USP 250 mg and 500 mg by reducing its absorption (7.1) Aluminum-based Antacids: May interfere with the action of ursodiol tablets, USP 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, USP 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, USP 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, USP 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, USP 250 mg and 500 mg.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION 17.1 Appropriate Treatments Patients with the following conditions should be instructed to receive appropriate management measures: variceal bleeding, hepatic encephalopathy, ascites, in need of an urgent liver transplant or hepatic function deterioration [see Warnings and Precautions (5) ]. Caution has to be exercised to maintain the bile flow of the patients taking ursodiol.. 17.2 Drug Interactions Patients should be informed that absorption of ursodiol tablets, USP 250 mg and 500 mg may be reduced if they are taking bile acid sequestering agents, such as cholestyramine and colestipol, aluminum-based antacids, or drugs known to alter the metabolism of cholesterol [see Drug Interactions (7) ].Manufactured by: Confab LaboratoriesSt-Hubert (Quebec) CANADADistributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USARevised: June 2018.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Ursodiol, naturally occurring hydrophilic bile acid, derived from cholesterol, is present as minor fraction of the total human bile acid pool. Oral administration of ursodiol increases this fraction in 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis Mutagen esis Impairment of Fertility In two 24-month oral carcinogenicity studies in mice, ursodiol at doses up to 1,000 mg/kg/day (3,000 mg/m2/day) was not tumorigenic. Based on body surface area, for 50 kg person of average height (1.46 m2 body surface area), this dose represents 5.4 times the recommended maximum clinical dose of 15 mg/kg/day (555 mg/m2/day). In two-year oral carcinogenicity study in Fischer 344 rats, ursodiol at doses up to 300 mg/kg/day (1,800 mg/m2/day, 3.2 times the recommended maximum human dose based on body surface area) was not tumorigenic. In life-span (126-138 weeks) oral carcinogenicity study, Sprague-Dawley rats were treated with doses of 33 to 300 mg/kg/day, 0.4 to 3.2 times the recommended maximum human dose based on body surface area. Ursodiol produced significantly (p<0.5, Fishers exact test) increased incidence of pheochromocytomas of the adrenal medulla in females of the highest dose group. In 103-week oral carcinogenicity studies of lithocholic acid, metabolite of ursodiol, doses up to 250 mg/kg/day in mice and 500 mg/kg/day in rats did not produce any tumors. In 78-week rat study, intrarectal instillation of lithocholic acid (1 mg/kg/day) for 13 months did not produce colorectal tumors. tumor-promoting effect was observed when it was administered after single intrarectal dose of known carcinogen N-methyl-N-nitro-N-nitrosoguanidine. On the other hand, in 32-week rat study, ursodiol at daily dose of 240 mg/kg (1,440 mg/m2, 2.6 times the maximum recommended human dose based on body surface area) suppressed the colonic carcinogenic effect of another known carcinogen azoxymethane. Ursodiol was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test, the human lymphocyte sister chromatid exchange test, the mouse spermatogonia chromosome aberration test, the Chinese hamster micronucleus test and the Chinese hamster bone marrow cell chromosome aberration test. Ursodiol at oral doses of up to 2,700 mg/kg/day (16,200 mg/m2/day, 29 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Ursodiol (UDCA) is normally present as minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of ursodiol is absorbed by passive diffusion and its absorption is incomplete. Once absorbed, ursodiol undergoes hepatic extraction to the extent of about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, ursodiol is conjugated with glycine or taurine, then secreted into bile. These conjugates of ursodiol are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some ursodiol is epimerized to chenodiol (CDCA) via 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. In healthy subjects, at least 70% of ursodiol (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated ursodiol to plasma protein in healthy subjects or PBC patients. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1% except in severe cholestatic liver disease. During chronic administration of ursodiol, it becomes major biliary and plasma bile acid. At chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.

POSTMARKETING EXPERIENCE SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 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, -GT increased, hepatic enzyme increased, liver function test abnormal, transaminases increased. Musculoskeletal and connective tissue disorders: myalgiaNervous system disorders: dizziness, headache.Respiratory, thoracic and mediastinal disorders: cough.Skin and subcutaneous tissue disorder: alopecia, pruritus, rash.. 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 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, -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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Reproduction studies have been performed in pregnant rats at oral doses up to 22 times the recommended maximum human dose (based on body surface area) and in pregnant rabbits at oral doses up to times the recommended maximum human dose (based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to ursodiol.There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.. 8.3 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 tablets, USP 250 mg and 500 mg are administered to nursing mother. 8.4 Pediatric Use The safety and effectiveness of ursodiol tablets, USP 250 mg and 500 mg in pediatric patients have not been established.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Patients with variceal bleeding, hepatic encephalopathy, ascites or in need of an urgent liver transplant, should receive appropriate specific treatment.. Patients with variceal bleeding, hepatic encephalopathy, ascites or in need of an urgent liver transplant, should receive appropriate specific treatment (5). Liver function tests (-GT, alkaline phosphatase, AST, ALT) and bilirubin level should be monitored. Treatment discontinuation should be considered if parameters increase to level considered clinically significant in patients with stable historical liver function test levels (5). Caution should be exercised to maintain patients bile flow (5).. Patients with variceal bleeding, hepatic encephalopathy, ascites or in need of an urgent liver transplant, should receive appropriate specific treatment (5). Liver function tests (-GT, alkaline phosphatase, AST, ALT) and bilirubin level should be monitored. Treatment discontinuation should be considered if parameters increase to level considered clinically significant in patients with stable historical liver function test levels (5). Caution should be exercised to maintain patients bile flow (5).. 5.1 Abnormal Liver Function Tests Liver function tests (-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 possible deterioration of the hepatic function. Treatment discontinuation should be considered if the above parameters increase to 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.