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Control No.

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 5 DRUG INTERACTIONS 6 DOSAGE AND ADMINISTRATION 6 OVERDOSAGE 7 ACTION AND CLINICAL PHARMACOLOGY 7 STORAGE AND STABILITY 8 DOSAGE FORMS, COMPOSITION AND PACKAGING 8

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION 9 CLINICAL TRIALS 9 DETAILED PHARMACOLOGY 13 TOXICOLOGY 14 REFERENCES 18

PART III: CONSUMER INFORMATION

Prpms-URSODIOL C Ursodiol Tablets USP 250 mg & 500 mg Cholestatic Liver Diseases

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Patients with variceal bleeding, hepatic encephalopathy, ascites, or in need of an urgent liver transplant, should receive appropriate specific treatment.

Ursodiol has no carcinogenic, mutagenic or teratogenic effects in laboratory animals treated at higher doses than those intended for therapy in human and after long-term treatment. See Product Monograph Part II: TOXICOLOGY - Carcinogenicity and Mutagenicity for discussion on animal data.

Pregnant Women:

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ursodiol should not be used in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus. (See also TOXICOLOGY Section)

Nursing Women:

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 is administered to a nursing mother.

Pediatrics

Geriatrics (> 65 years of age):

Appropriate studies with ursodiol have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of ursodiol in the elderly are not expected.

Monitoring and Laboratory Tests:

Cholestatic liver diseases are characterized by a decrease in bile secretion and bile flow. The diagnosis of cholestatic liver diseases is based on the biochemical signs of cholestais (such as an increase in alkaline phosphatase, (-GT, bilirubin), and also an incease in IgM levels and the presence of antimitochondrial antibodies in PBC. The monitoring of the efficacy of ursodiol in the management of cholestatic liver diseases should be based on the biochemical parameters of cholestasis, as described above, as well as on signs of hepatic cytolysis (such as AST, ALT) which are very often associated with cholestasis during the progression of the disease. Lithocholic acid, the metabolite of ursodeoxycholic acid (ursodiol) is hepatotoxic unless it is effectively detoxified in the liver. Therefore, the following tests are important for patient monitoring: Liver function tests ((-GT, alkaline phosphatase, AST, ALT), and bilirubin level should be monitored every month for three months after start of therapy, and every six months thereafter. Serum levels of these parameters usually decrease rapidly thus demonstrating efficacy. Treatment should be discontinued if the levels of above parameters increase.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not

be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Adverse Events	Visit at 12 Months		Visit at 24 Months
Adverse Events	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)	-

Note: The above adverse reactions were observed in clinical trials in primary biliary cirrhosis with 180 patients (89 randomized to ursodiol treatment, 91 to placebo treatment). Adverse reactions occurring at a rate of 1% or higher in the ursodiol group and that are higher than placebo are included in the above table. Diarrhea and thrombocytopenia at 12 months, nausea/vomiting, fever and other toxicity are not included because they occurred at the same rate or a lower rate than placebo. UDCA = Ursodeoxycholic acid = Ursodiol = pms-URSODIOL C In a randomized, cross over study in sixty PBC patients, four patients experienced one serious adverse event each (diabetes mellitus, cyst and breast neoplasm (experienced by two patients)). No deaths occurred in the study. Forty-three patients (43, 71.7%) experienced at least one treatment- emergent adverse event (TEAEs) during the study. The most common (>5%) TEAEs were asthenia, (11.7%), dyspepsia (10%), peripheral oedema (8.3%), hypertension (8.3%), nausea (8.3%), GI disorders (5%), chest pain (5%), and pruritus (5%). These nine TEAEs included abdominal pain and asthenia (1 patient), nausea (3 patients), dyspepsia (2 patients), and anorexia and oesophagitis (1 patient each). One patient on the BID regimen (total dose 1000 mg) withdrew due to nausea. All of these nine TEAEs except oesophagitis were observed with the BID regimen at a total daily dose of 1000 mg or greater.

Post-Market Adverse Drug Reactions

Most of the serious adverse events were received from Japan. These adverse events occurred in patients taking ursodiol (ursodeoxycholic acid) with a different formulation, however, containing the same active ingredient as that contained in product marketed in North America (ursodiol). In Japan, ursodiol is indicated for PBC and other hepatic conditions. Interstitial pneumonia was included in the Japanese product labeling due to the frequency of its occurrence. There have been rare reports from Japan of hepatic function disorder, thrombocytopenia and haemolytic anemia. Very rare cases of melena and hip fracture have been reported in the US. It is not possible to determine the causality and frequency of reported events attributed to ursodiol due to the uncontrolled nature of post- marketing surveillance.

DRUG INTERACTIONS

Bile acid sequestrants such as cholestyramine or colestipol may interfere with the action of ursodiol by reducing its absorption.

Antacids: Aluminum based antacids have been shown to absorb bile acid in vitro and may be expected to interfere with ursodiol in the same manner as the sequestering agents.

There was no clinically significant effect of food on the bioavailability of ursodiol.

There are no known interactions of ursodiol with commonly used laboratory tests.

DOSAGE AND ADMINISTRATION

The recommended adult dosage for pms-URSODIOL C in the treatment of PBC is 13 to 15 mg/kg/day administered in two to four divided doses with food.

P l e a s e i n s t r u c t p a t i e n t s t h a t i f a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Patients should be instructed to not double dose.

OVERDOSAGE

Accidental or intentional overdosage with ursodiol has not been reported. The most severe manifestation of overdosage would likely consist of diarrhea which should be treated symptomatically. Symptoms of acute toxicity in animal studies were salivation and vomiting in dogs, and ataxia, dyspnea, ptosis, agonal convulsions and coma in hamsters.

ACTION AND CLINICAL PHARMACOLOGY

pms-URSODIOL C (ursodiol), a naturally occurring bile acid, is present as a minor fraction of the total human bile acids. Oral administration of ursodiol increases this fraction in a dose related manner, to become the major biliary acid. The cholesterol-lowering effect observed following the administration of ursodiol in patients with primary biliary cirrhosis could be related to an improvement of cholestasis, modifications in cholesterol metabolism, or both. Changes in the endogenous bile acid composition induced by ursodiol might be the common denominator of these two mechanisms.

Ursodiol (UDCA) is normally present as a 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 a 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. 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 ben associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals. Nonetheless, such a deficiency has not yet been clearly demonstrated and must be extremely rare, given the several thousand patient-years of clinical experience with ursodiol. 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 primary biliary cirrhosis (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 a major biliary and plasma bile acid. At a chronic dose of 13-15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.

STORAGE AND STABILITY

pms-URSODIOL C tablets should be stored at controlled room temperature, 15o to 30oC in a closed container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

pms-URSODIOL C is available as white, eliptical, biconvex, coated tablet engraved with "250" on one side and "P" logo on the other side, in strength of 250 mg in high density polyethylene bottles. Available in bottles of 100 and 500 tablets. pms-URSODIOL C is available as white, eliptical, biconvex, coated tablet ink-printed in black with "P" logo on one side and "500" on the other side, in strength of 500 mg in high density polyethylene bottles. Available in bottles of 100 tablets.

pms-URSODIOL C Tablets contain the following inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, sodium starch glycolate.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
oral	tablet 250 mg, 500 mg	None For a complete listing see Dosage Forms, Composition and Packaging section.

PRODUCT MONOGRAPH

Cholestatic Liver Diseases

PHARMASCIENCE INC. DATE OF PREPARATION: