URSO®

Ursodiol Tablets 250 mg

DESCRIPTION

URSO® is a bile acid available as 250 mg film-coated tablets for
oral administration.

URSO® is ursodiol (ursodeoxycholic acid), 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 3a,7ß-dihydroxy-5ß-cholan-24-oic
(C24H40O4). 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.

CLINICAL PHARMACOLOGY

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 been 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.

CLINICAL STUDIES

A U.S., multicenter, randomized, double-blind, placebo-controlled study was
conducted to evaluate the efficacy of ursodeoxycholic acid at a dose of 13-15
mg/kg/day, administered in 4 divided doses in 180 patients with PBC. Upon completion
of the double-blind portion, all patients entered an open-label active treatment
extension phase.

Treatment failure, the main efficacy end point measured during this study,
was defined as death, need for liver transplantation, histologic progression
by two stages or to cirrhosis, development of varices, ascites or encephalopathy,
marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling
of serum bilirubin and voluntary withdrawal. After two years of double-blind
treatment, the incidence of treatment failure was significantly reduced in the
URSO® group (n=89) as compared to the placebo group (n=91). Time to treatment
failure was also significantly delayed in the URSO® treated group regardless
of either histologic stage or baseline bilirubin levels (>1.8 or £
1.8 mg/dl).

Using a definition of treatment failure which excluded doubling of serum bilirubin
and voluntary withdrawal, time to treatment failure was significantly delayed
in the URSO® group. In comparison with placebo, treatment with URSO®
resulted in a significant improvement in the following serum hepatic biochemistries
when compared to baseline: total bilirubin, SGOT, alkaline phosphatase and IgM.

A second study conducted in Canada randomized 222 PBC patients to ursodiol,
14 mg/kg/day or placebo, in a double-blind manner during a two-year period.
At two years, a statistically significant difference between the two treatments,
in favor of ursodiol, was demonstrated in the following: reduction in the proportion
of patients exhibiting a more than 50% increase in serum bilirubin; median percent
decrease in bilirubin, transaminases and alkaline phosphatase; incidence of
treatment failure; and time to treatment failure. The definition of treatment
failure included: discontinuing the study for any reason; a total serum bilirubin
level greater than or equal to 1.5 mg/dl or increasing to a level equal to or
greater than two times the baseline level; and the development of ascites or
encephalopathy.

INDICATIONS AND USAGE

URSO® (ursodiol) tablets are indicated for the treatment of patients with
primary biliary cirrhosis.

CONTRAINDICATIONS

Hypersensitivity or intolerance to ursodiol or any of the components of the
formulation.

PRECAUTIONS

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

Drug Interactions

Bile acid sequestering agents such as cholestyramine and colestipol may interfere
with the action of URSO® by reducing its absorption. Aluminum-based antacids
have been shown to adsorb bile acids in vitro and may be expected to interfere
with URSO® 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 URSO®.

Carcinogenicity, Mutagenicity and 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 a 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 a 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 a 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 a significantly
(p£0.5, Fisher’s 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, a 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 a 78-week rat study, intrarectal instillation of
lithocholic acid (1 mg/kg/day) for 13 months did not produce colorectal tumors.
A tumor-promoting effect was observed when it was administered after a single
intrarectal dose of a known carcinogen N-methyl-N’-nitro-N-nitrosoguanidine.
On the other hand, in a 32-week rat study, ursodiol at a 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.

Pregnancy, Teratogenic Effects. Pregnancy Category B

Teratology studies have been performed in pregnant rats at oral doses up to
2,000 mg/kg/day (12,000 mg/m2/day, 22 times the recommended maximum human dose
based on body surface area) and in pregnant rabbits at oral doses up to 300
mg/kg/day (3,600 mg/m2/day, 7 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.

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 URSO® is administered
to a nursing mother.

Pediatric Use

The safety and effectiveness of URSO® in pediatric patients have not been
established.

OVERDOSE

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.

Single oral doses of ursodiol at 10, 5 and 10 g/kg in mice, rats and dogs,
respectively 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.

DOSAGE AND ADMINISTRATION

The recommended adult dosage for URSO® in the treatment of PBC is 13-15
mg/kg/day administered in four divided doses with food.

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HOW SUPPLIED

Each URSO® film-coated tablet, white, engraved with “URS785”, contains
250 mg of ursodiol. Available in bottles of 100 tablets (NDC 0091-0785-01).
Store at 20 °C to 25 °C (68 °F to 77 °F). Dispense in a tight
container. Caution: Federal law prohibits dispensing without a prescription.

Manufactured by:

GLOBAL PHARM INC.

North York, Ontario M3B1Y5

Canada

for:

AXCAN PHARMA U.S. INC.

3940 Quebec Avenue North

Minneapolis, MN 55427

USA

Distributed by:

SCHWARZ PHARMA

Milwaukee, WI 53201

USA

® Reg. TM of Axcan Pharma U.S. Inc

April 1998

Printed in Canada.