Urso

Interactions with herbal products have not been established.

Interactions with food have not been established.

Interactions with laboratory tests have not been established.

Bile acid sequestering agents may interfere with the action of URSO and URSO DS by reducing absorption. Aluminum based antacids adsorb bile acids in vitro and may act in the same manner as sequestering agents, thereby interfering with the action of URSO and URSO DS. Ursodiol has been shown to be an inducer of CYP3A however the clinical relevance is not known. Metabolic interactions with compounds metabolized by cytochrome P4503A are to be expected.

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 then every six months. Serum levels of these parameters usually decrease rapidly, thus, demonstrating efficacy. Treatment should be discontinued if the levels of the above parameters increase.

The recommended adult dosage for URSO and URSO DS (ursodiol) in the treatment of PBC is 13-15 mg/kg/day administered in two to four divided doses with food.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the dose you missed and take your next regularly scheduled dose. Do not take a double dose.

All the non-hepatic clinical chemistries at baseline were not significantly different (p>0.05) between the UDCA- and placebo-treated groups. In the UDCA group there was a significant (p>0.05) decrease from baseline in calcium, cholesterol and total thyroxine and a significant increase (p>0.05) in creatinine and triglycerides. In the placebo group there was a significant (p>0.05) decrease in cholesterol and significant increase (p>0.05) in calcium and creatinine. There was no significant change seen for sodium, potassium, phosphorus, HDL, and AMA.

Treatment-Emergent Adverse Events (TEAEs) with a Frequency of ≥1 % Observed in a Clinical Trial of 60 PBC Patients

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 (URSO). 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 hemolytic anemia. Very rare cases of melena and hip fracture have been reported in the U.S. It is not possible to determine the causality and frequency of reported events attributed to URSO due to the uncontrolled nature of post-marketing surveillance.

A review of the literature revealed specific findings of adverse events and drug interactions [see Drug Interactions]. This analysis listed abdominal pain in upper right quadrant, diarrhea, flatulence, nausea and vomiting as recorded adverse events. It also noted decompensation of liver cirrhosis in single cases of late-stage PBC during UCDA treatment.

Adverse events observed in clinical trials are tabulated and described below. In a 180 patient placebo-controlled trial in primary biliary cirrhosis, the common adverse events (i.e. ≥1 %) included leukopenia, skin rash, diarrhea, blood creatinine increased, blood glucose increased, and peptic ulcer. In a second trial with 60 patients, the frequency of treatment-emergent adverse event reporting was higher with the most common (defined as ≥5%) being asthenia, dyspepsia, edema peripheral, hypertension, nausea, GI disorder, chest pain, and pruritus. In this second trial there were 4 serious adverse events: 1 patient with diabetes mellitus, 1 patient with breast nodule and 2 patients with fibrocystic breast disease. None of these events were considered related to the medication. At the recommended dosage, ursodiol is well-tolerated and has no significant adverse events.

Analysis of the data in the trial with 180 patients (Table 1) revealed no reports of adverse events at rates <1 % with the exception of those adverse events that occurred at the same or at a higher incidence in the treatment group than placebo. No data for TEAEs occurring at rates <1 % in the trial of 60 patients (Table 2) are available due to the small sample size.

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

The safety and effectiveness of URSO and URSO DS in children have not been established.

Each white, elliptical, biconvex, film-coated tablet, engraved with “URS785” on one side, contains: ursodiol USP 250 mg. Nonmedicinal ingredients: carnauba wax, dibutyl sebacate, ethylcellulose aqueous (cetyl alcohol, ethylcellulose, hydrogen peroxide, sodium lauryl sulfate), hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and sodium starch glycolate. Bottles of 100.

Each white, elliptical, biconvex, film-coated tablet, engraved with “URS790” on one side, contains: ursodiol USP 500 mg. Nonmedicinal ingredients: carnauba wax, dibutyl sebacate, ethylcellulose aqueous (cetyl alcohol, ethylcellulose, hydrogen peroxide, sodium lauryl sulfate), hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and sodium starch glycolate. Bottles of 100.

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

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

URSO and URSO DS have no carcinogenic, mutagenic or teratogenic effects in laboratory animals treated at higher doses than those intended for therapy in humans, and after long-term treatment.

The safety and effectiveness of URSO and URSO DS in children have not been established.

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, URSO and URSO DS 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 apprised of the potential hazard to the fetus.

It is not known whether ursodiol is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when URSO or URSO DS is administered to a nursing mother.

Lithocholic acid, one of the metabolites of ursodeoxycholic acid (URSO and URSO DS) is hepatotoxic unless it is effectively detoxified in the liver. Therefore, the following tests are important for patient monitoring:

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. Serum levels of these parameters usually decrease rapidly, thus, demonstrating efficacy. Treatment should be discontinued if the levels of the above parameters increase.

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. However, since the efficacy of ursodiol is related to its concentration in bile rather than in plasma, serum levels are not indicative of bioavailability in clinical settings. 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. In bile, UDCA concentration reaches a peak in 1-3 hours.

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.

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.

Multiple mechanisms of action at the cellular and molecular level in addition to the replacement and displacement of toxic bile acids include cytoprotection of the injured bile duct epithelial cells (cholangiocytes) against toxic effects of bile acids, inhibition of apotosis of hepatocytes, immunomodulatory effects via a number of mechanisms including decreasing expression of MHC class I proteins on hepatocytes and cholangiocytes, and stimulation of bile secretion by hepatocytes and cholangiocytes.

The cholesterol-lowering effect observed following the administration of URSO and URSO DS 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 URSO and URSO DS might be the common denominator of these two mechanisms.

During chronic administration, ursodiol 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.

Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1%, except in severe cholestatic liver disease.

Once absorbed, ursodiol undergoes hepatic extraction to the extent of about 70% in the absence of liver disease. This leads to low blood levels in the systemic circulation. 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.