urso
Generic Name: (
ursodiol)
Dosage Type: tablet, film coated urso forte
Generic Name: (
ursodiol)
Dosage Type: tablet, film coated Organization: Axcan Scandipharm Inc.
DESCRIPTION
URSO 250® (ursodiol, 250 mg) and URSO Forte™
(ursodiol, 500 mg) are available as film-coated tablets 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 3a,7ß-dihydroxy-5ß-cholan-24-oic
(C24 H40 O4). 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 to 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 to 15 mg/kg/day, administered in 3 or 4 divided doses in 180 patients
with PBC (78% received QID dosage). 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 250® group (n=89) as compared to the placebo group
(n=91). Time to treatment failure was also significantly delayed in the URSO
250® 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 250® group. In comparison with placebo, treatment
with URSO 250® 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, administered as a once daily dose 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. Evaluation of patients
at 4 years or longer was inadequate due to the high drop out rate and small
number of patients. Therefore, death, need for liver transplantation, histological
progression by two stages or to cirrhosis, development of varices, ascites
or encephalopathy, marked worsening of fatigue or pruritis, inability to tolerate
the drug, doubling of serum bilirubin and voluntary withdrawal were not assessed.
A
randomized, two-period crossover study in fifty PBC patients compared efficacy
of URSO 250® (ursodiol) in BID (two) versus QID (four) divided
dosing schedules in 50 patients for 6 months in each crossover period. Mean
percent changes from baseline in liver test results and Mayo risk score (n=46)
and serum enrichment with UDCA (n=34) were not statistically significant with
any dosage at any time interval. This study demonstrated that UDCA (13 to
15 mg/kg/day) given BID is equally effective to UDCA given QID. In addition,
URSO 250® was given as a single (once daily) versus TID
(three) dosing schedules in 10 patients. Due to the small number of patients
in this arm of the study, it was not possible to conduct statistical comparisons
between these regimens.
INDICATIONS AND USAGE
URSO 250® and URSO Forte™ (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 250® and
URSO Forte™ by reducing its absorption. Aluminum-based antacids have
been shown to adsorb bile acids in vitro and
may be expected to interfere with URSO 250® and URSO Forte™
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 250® and URSO Forte™.
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 250® and URSO Forte™ are administered to
a nursing mother.
Pediatric Use
The safety and effectiveness of URSO 250® and
URSO Forte™ in pediatric patients have not been established.
ADVERSE EVENTS (AEs)
The following table summarizes the AEs observed in the two
placebo-controlled clinical trials.
|
ADVERSE
EVENTS
|
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)
|
---
|
Note: Those AEs 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, four patients (6.7%) 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 edema (8.3%), hypertension (8.3%), nausea (8.3%), GI disorders
(5%), chest pain (5%), and puritius (5%). Seven patients (11.6%) reported
nine events that were judged as possibly or probably related to study medication.
These nine TEAEs included abdominal pain and asthenia (1 patient), nausea
(3 patients), dyspepsia (2 patients) and anorexia and esophagitis (1 patient
each). One patient on the BID regimen (total dose 1000 mg) withdrew due to
nausea. All of these nine TEAEs except esophagitis were observed with the
BID regimen at a total daily dose of 1000 mg or greater.
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 250® and
URSO Forte™ 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 patient’s need at the discretion of the physician.
HOW SUPPLIED
Each URSO 250® elliptical, biconvex, film-coated
tablet, white, engraved with "URS785", contains 250 mg of ursodiol. Available
in bottles of 100 tablets (NDC 58914-785-10) and 500 tablets (NDC 58914-785-50).
Each
URSO Forte™ elliptical, biconvex, film-coated tablet, white, engraved
with "URS790", contains 500 mg of ursodiol. Available in bottles of 100 tablets
(NDC 58914-790-10) and 500 tablets (NDC 58914-790-50).
Store
at 20°C to 25°C (68°F to 77°F).
Dispense in a tight container.
Manufactured
in Canada for:
Axcan Scandipharm Inc.
22 Inverness Center
Parkway
Birmingham, AL 35242 USA
URSO 250® and
URSO Forte™ are trademarks of Axcan Pharma US Inc. July 21, 2004
Printed in Canada.
Revised: 04/2006Axcan Scandipharm Inc.