Urso Forte Ursodiol 500 mg Tablet, Film Coated, 4-count — NDC 58914-790-01 (Billing 58914-0790-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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. 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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. 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 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.

12.1Mechanism of Action 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. 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.

12.3Pharmacokinetics 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. 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 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.

12.2Pharmacodynamics 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.

6.1Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 REACTIONS 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) --- 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 a 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 a day regimen (total dose 1,000 mg) withdrew due to nausea. All of these nine adverse reactions except esophagitis were observed with the twice a day regimen at a total daily dose of 1,000 mg or greater.

However, an adverse reaction may occur at any dose.

14 CLINICAL STUDIES

14.1Efficacy of Ursodeoxycholic Acid A dministered at 13 to 15 mg/kg/day in 3 or 4 Divided Doses to PBC Patients 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 four times a day dosage). Upon completion of the double-blind portion, all patients entered an open-label active treatment extension phase. Treatment failure, the main efficacy endpoint 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 (p<0.01) reduced in the URSO 250 mg group (20 of 86 (23%) as compared to the placebo group (40 of 86 (47%). Time to treatment failure, which excluded doubling of serum bilirubin and voluntary withdrawal, was also significantly (p<0.001) delayed in the URSO 250 treated group (n=86, 803.8±24.9 d vs. 641.1±24.4 d for the placebo group (n=86) on average) 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.

14.2Efficacy of Ursodiol Administered at 14 mg/kg/day as a Once Daily Dose to PBC Patients 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 (p<0.001) difference between the two treatments (n=106 for the URSO 250 group and n=106 for the placebo group), 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… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, 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/m 2 /day) was not tumorigenic. Based on body surface area, for a 50 kg person of average height (1.46 m 2 body surface area), this dose represents 5.4 times the recommended maximum clinical dose of 15 mg/kg/day (555 mg/m 2 /day). In a two-year oral carcinogenicity study in Fischer 344 rats, ursodiol at doses up to 300 mg/kg/day (1,800 mg/m 2 /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/m 2 , 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/m 2 /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.