Novo-Ursodiol Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Novo-Ursodiol (ursodiol, also known as ursodeoxycholic acid (UDCA)) is indicated for:

• the management of cholestatic liver diseases, such as primary biliary cirrhosis (PBC).

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 cholestasis (such as an increase in alkaline phosphatase, γ-GT, bilirubin), and also an increase in IgM levels and the presence of antimitochondrial antibodies in PBC.

The monitoring of the 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 diseases. 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 (γ-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. Improved serum liver tests (e.g. ALP, AST) do not always correlate with improved disease status. Treatment should be discontinued if the levels of the above parameters increase (see WARNINGS and PRECAUTIONS).

NOVO-URSODIOL is not indicated for the treatment of decompensated cirrhosis.

Geriatrics:

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.

Pediatrics:

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

CONTRAINDICATIONS

Patients who are hypersensitive or intolerant to ursodiol or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

WARNINGS AND PRECAUTIONS

Carcinogenesis and Mutagenesis

Ursodiol has 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 (see TOXICOLOGY).

Hepatic/Biliary/Pancreatic

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

Special Populations

Pregnant Women: There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, NOVO-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 apprised of the potential hazard to the foetus. (See also TOXICOLOGY.)

Nursing Women:

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

Pediatrics:

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

Geriatrics: 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

Lithocholic acid, one of the metabolites 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 (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. Improved serum liver tests (e.g. ALP, AST) do not always correlate with improved disease status. Treatment should be discontinued if the levels of the above parameters increase.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

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.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse 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.

The adverse reactions in Table 1 below were observed in clinical trials in primary biliary cirrhosis with 180 patients (89 randomized to ursodiol treatment, 91 to placebo treatment). Adverse events are reported regardless of attribution to the test medication. Adverse reactions occurring at a rate of 1% or higher in the ursodiol group, and that are higher than placebo are included in Table 1. Diarrhea and thrombocytopenia at 12 months, nausea/vomiting, fever and other side effects are not included, because they occurred at the same rate or a lower rate than placebo.

Table 1: Adverse events with a frequency ≥ 1% Observed in a Clinical Trial of 180 patients

1

UDCA=Ursodeoxycholic acid=Ursodiol

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).

In a randomized, cross over study in sixty PBC patients, four patients experienced one serious adverse event each (diabetes mellitus, breast nodule, and fibrocystic breast disease (2 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 (defined as ≥5%) TEAEs were asthenia, (11.7%), dyspepsia (10%), edema peripheral (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 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.

Table 2: Treatment-Emergent Adverse Events (TEAEs) with a Frequency of ≥ 1 % Observed in a Clinical Trial of 60 PBC patients

Less Common Clinical Trial Adverse Drug Reactions (<1%)

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.

Abnormal Hematologic and Clinical Chemistry Findings

In the placebo-controlled trial with 180 patients, change from baseline in hematologic parameters and non-hepatic clinical chemistry were analyzed. Statistically significant differences from baseline are reported in Tables 3 and 4.

Table 3: Hematologic Parameters: Changes from Baseline

There was a significant decrease (p<0.01) in WBC and platelets in the UDCA-treated group from baseline and a significant (p<0.05) decrease in platelets in the placebo group. There was no significant change in haemoglobin.

Table 4: Clinical Chemistries: Changes from Baseline

** Statistically different from zero, p < 0.01

* Statistically different from zero, p < 0.05

^ap = ns, UDCA versus placebo

^bp = 0.0001, UDCA versus placebo

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.

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 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 ursodiol 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.

DRUG INTERACTIONS

Overview

Bile acid sequestering agents may interfere with the action of ursodiol 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 ursodiol. 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.

Drug-Drug Interactions

Table 5: Drug-Drug Interactions

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

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 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.

Recommended Dose

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

Missed Dose

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.

OVERDOSAGE

Accidental or intentional overdosage with ursodiol has not been reported. The most severe manifestation of overdosage would likely consist of diarrhea that 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism 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.

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 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.

Pharmacodynamics

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.

Pharmacokinetics

Absorption: 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.

Distribution: 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.

Metabolism: 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.

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

STORAGE AND STABILITY

NOVO-URSODIOL tablets should be stored at controlled room temperature (15° - 30°C) in a closed container.

SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

DOSAGE FORMS, COMPOSITION AND PACKAGING

250 mg tablet

Novo-Ursodiol is available in strength of 250 mg as white to off-white, oval shaped, film coated tablet, debossed with “93” on one side of the tablet and with “5360” on the other side of the tablet. They are supplied in HDPE bottles containing 100 and 500 tablets and in unit dose of 100 tablets.

500 mg tablet

Novo-Ursodiol is available in strength of 500 mg as white to off-white, oval shaped, film coated tablet, debossed with “93” on one side of the tablet and with “5361” on the other side of the tablet. They are supplied in HDPE bottles containing 100 and 500 tablets and in unit dose of 100 tablets.

In addition to ursodiol as the active ingredient, Novo-Ursodiol contains the following excipients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulphate, sodium starch glycolate, hypromellose, Ethylcellulose, cetyl alcohol, dibutyl sebacate.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ursodiol

Chemical name: 3α, 7β-dihydroxy-5β-cholan-24-oic acid

Molecular formula and molecular mass: C₂₄H₄₀O₄ 392.6

Structural formula:

Physicochemical properties:

Description: Ursodiol is a naturally occurring bile acid in man. Ursodiol is a bitter-tasting, white, crystalline powder.

Solubility: Ursodiol is practically insoluble in water, freely soluble in alcohol and glacial acetic acid, slightly soluble in chloroform, and very slightly soluble in ether.

Melting Range: 200° - 205°C

pKa: 6.0

pH: Alkaline

CLINICAL TRIALS

This is a single-dose (1x500 mg), crossover study to evaluate the comparative bioavailability between Novo-Ursodiol (ursodiol) 500 mg Tablets (Novopharm Limited) and URSO DS^TM

(ursodiol) 500 mg Tablets (Axcan Pharma Inc., Canada) in 53 healthy, non-smoking, male and female subjects under fasting conditions.

^πDue to the nature of the active ingredient, meaningful estimates of the AUC₁ and T_1/2 parameters could not be derived, and are therefore not reported.

^I T = 72 hours

^* Novo-Ursodiol (ursodiol) 500 mg tablets (Novopharm Limited) ^† URSO DS™ (ursodiol) 500 mg tablets (Axcan Pharma Inc., Canada, purchased in Canada) ^§ Expressed as the arithmetic mean (CV%) only

^# Based on the least squares mean estimates

Study demographics and trial design:

Table 6: Summary of patient demographics for clinical trials in primary biliary cirrhosis (PBC)

¹ UDCA = Ursodeoxycholic acid = Ursodiol

U.S. Study: A 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 ursodiol group (n=89) as compared to the placebo group (n=91). Time to treatment failure was also significantly delayed in the ursodiol 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 ursodiol group. In comparison with placebo, treatment with ursodiol resulted in a significant improvement in the following serum hepatic biochemistries when compared to baseline: total bilirubin, AST, alkaline phosphatase and IgM.

Canadian Study: A second study conducted in Canada randomized 222 PBC patients to ursodiol 14 mg/kg/day (n=111) or placebo (n=111), 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 by 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 pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal were not assessed.

Multinational Study: A two-year multicenter, multinational (France-Canada), double-blind study was conducted to compare the efficacy of ursodiol versus placebo in primary biliary cirrhosis. Patients with histologically confirmed biliary cirrhosis were randomized to receive either ursodiol 13-15 mg/kg/day (n=72), or placebo (n=73). Treatment failure was defined as a doubling of bilirubin levels (>70 μmol/L) or the occurrence of severe complications (ascites or variceal bleeding) or an adverse event.

The results showed that treatment failed in six patients in the ursodiol group, as compared with thirteen in the placebo group (p<0.01). A single patient in each group withdrew because of minor adverse effects. After two years of treatment, the proportion of patients with clinically overt disease decreased only in the ursodiol group (p<0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, cholesterol, and IgM (all p<0.01); the antimitochondrial antibody titer (p<0.01); and the Mayo risk score (p<0.001). In a follow-up analysis of 95 liver-biopsy specimens, only the group receiving ursodiol showed a significant improvement in the mean histologic score (p<0.002) and in all the characteristic histologic features except fibrosis.

At the end of this trial, all patients received ursodiol (13-15 mg/kg/day) and were monitored for an additional two years, using the same criteria.

After four years, the overall treatment failure rate was 12% in the ursodiol group and 26% in the original placebo group (p<0.001). Two patients in the ursodiol group had undergone a liver transplantation, compared to 12 in the original placebo group (p<0.001). Survival was similar in the two groups: 5 deaths (various causes) occurred in the ursodiol group and 7 in the original placebo group.

Combined Analysis: The raw data from the above three studies have been combined in order to estimate, at four years, the magnitude of the effect of ursodiol treatment on survival free of transplant, defined as time to transplant, or death without transplant.

In these studies, all patients had histologically confirmed, antimitochondrial antibody positive, primary biliary cirrhosis. They were randomized to receive ursodiol (13-15 mg/kg/day) or identical placebo. In one study, blinded randomization continued for four years. In two studies, open label ursodiol was offered to all patients after two years. The endpoint of survival free of liver transplant was compared between the ursodiol and placebo groups using standard life table analyses. Analyses were done on an "intent-to-treat" basis. The risk reduction was calculated in order to define the magnitude of the benefit from ursodiol treatment.

A total of 548 patients were randomized in these studies: 273 received ursodiol and 275, the placebo. Baseline characteristics were comparable at entry in both groups. Median length of follow-up was four years in the ursodiol group, and 3.8 years in the original placebo group. Placebo patients who received ursodiol did so for a mean of one year. There were 47 patients in the ursodiol group and 68 in the placebo group who did not survive or needed a liver transplant. Survival free of transplantation was extended in patients originally randomized to ursodiol when compared to those on placebo (mean of 3.66 versus 3.45 years, p=0.014). In the ursodiol group the risk of dying or being transplanted was reduced by 32% (± 11%) of that observed in the original placebo group.

Clinical Trial: Unapproved High-Dose Ursodeoxycholic Acid for the Treatment of Primary Sclerosing Cholangitis:In a recent Clinical Trial, one hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high dose (28-30 mg/kg/day

• 1.5 to 2 fold the recommended dose) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the ursodeoxycholic acid group than the placebo group (P<0.01), but improvements in liver tests were not associated with decreased endpoints. By the end of the study, 30 patients in the ursodeoxycholic acid group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. The risk was 2.1 times greater for death and transplantation in the ursodeoxycholic acid group versus the placebo group (P=0.038). Serious adverse events were more common in the ursodeoxycholic acid group than the placebo group (63% versus 37% [P<0.01]). Long-term, high-dose ursodeoxycholic acid therapy is associated with improvement in serum liver tests in PSC but does not improve survival and was associated with higher rates of serious adverse events.*

*Lindor, K.D., et. al. Hepatology, 2009, 50(3), 808-814.

DETAILED PHARMACOLOGY

Administration of ursodiol to rats, rabbits, hamsters and dogs produced modification of bile composition. Bile flow increased as did total bile acid output. In the liver, ursodiol decreased HMG-CoA reductase activity and cholesterol 7-hydroxylase activity. Triglyceride, phospholipid and cholesterol synthesis were decreased.

Studies have demonstrated that ursodiol acts on the hepatic cells and plays a role in the bile acid dependent mechanism of bile formation. Its choleretic activity results from its osmotic activity as well as its stimulating effect on organic ion transport (probably HCO₃).

In vitro studies showed that tauroursodeoxycholic acid (i.e. in the liver ursodiol is conjugated with taurine or glycine) decreased cholesterol uptake in rat jejunal membranes by an unknown mechanism. When ursodiol was perfused into the liver of rats or baboons, bile flow either remained unchanged or increased, bile acid and phospholipid outputs were increased, while cholesterol specific activity was decreased. Tauroursodeoxycholic acid caused only little output of plasma membrane enzyme concentration (5-nucleotidase and alkaline phosphatase), which may represent a characteristic difference between the effects of chenodiol and ursodiol on the hepatobiliary system.

Ursodiol produced minimal or no effect on water and sodium excretion from the GI tract of rats and rabbits. It induced less damage to the GI tract mucosa than chenodiol. These observations correlate well with the clinical findings that diarrhea is infrequent with ursodiol.

Ursodiol lowered blood sugar levels in mice, and increased the volume of pancreatic secretion in rabbits, thus suggesting a stimulatory effect of ursodiol on the pancreas.

At therapeutic doses, ursodiol uncouples the normal relationship between cholesterol, phospholipids and bile acid secretion. Ursodiol inhibits cholesterol absorption in the gut, thereby, reducing cholesterol output into the bile. It further reduces cholesterol secretion into bile. These actions contribute to biliary cholesterol desaturation.

TOXICOLOGY

Acute Toxicity

Results from various studies indicated that oral, subcutaneous, intraperitoneal and intravenous administration of ursodiol in mice, rats, hamsters, and dogs at single doses of 1.21 to 10 g/kg over a seven-day observation period, did not cause any deaths in any of the species used. For mice and dogs, the LD₅₀ was >10 g/kg, and rats had an LD₅₀ over >5 g/kg. Hamsters were found to be more sensitive than rats and dogs as the LD₅₀ for this species was calculated to be >3.16 g/kg.

No significant sex difference was seen. Toxic signs observed included: inhibition of motility, CNS toxicity such as ataxia and sedation, GI tract disturbances such as vomiting, salivation, decreased body weight and appetite.

Subacute Toxicity

Two short-term toxicological studies were conducted in rats. Ursodiol was administered orally at a daily dose of 0.5 to 4.0 g/kg/day for five weeks or alternatively at doses of 0.0625 to 0.5 g/kg daily for five weeks by the intraperitoneal route.

No deaths occurred in the study with oral administration of ursodiol, whereas, one male and one female rat died in the 0.25 g/kg group, and six males and four females died in the 0.5 g/kg group of the study in which ursodiol was administered by the intraperitoneal route. The most marked autopsy findings were dilation and adhesion of intraperitoneal organs. As these became gradually more severe, retention of ascites and renal abscesses appeared. It was concluded that 0.0625 g/kg was the safe dose and 0.125 g/kg was near the maximum tolerable dose.

Ursodiol orally administered to rats did not cause any clinical symptoms or any changes in laboratory parameters

Chronic Toxicity

Four long-term toxicity studies were performed in rats and monkeys. The results of these studies are summarized below.

Rat Study: In one study, ursodiol was administered orally to Sprague-Dawley rats for 26 weeks. The dosage varied between 0.1 and 2.5 g/kg/day and various observations were performed daily.

No deaths occurred during the experimental period. Lower doses (0.1 and 0.5 g/kg) were well tolerated. However, a 2.5 g/kg dose of ursodiol resulted in significant reduction of body weight gain and food intake. No significant changes were seen in laboratory findings and clinical observations.

In the second study, male Wistar rats were given 0.5 to 4.0 g/kg of ursodiol orally for 26 consecutive weeks and a variety of observations were made.

The results indicated a decrease in body weight gain and an increase in water intake in the 4.0 g/kg dosage group. Eight rats (four at the high dose level) died during the experiment. The cause of death was attributed to pathological changes in the lung and intestine. Laboratory findings revealed no abnormal changes that might be ascribed to drug administration.

Monkey study: A 26-week study was performed in Rhesus monkeys. Ursodiol at doses of 0.04 and 0.10 g/kg/day were given orally.

No deaths occurred during the treatment period. There were no abnormalities in the laboratory parameters.

In a 52-week study, ursodiol at a dose of 0.05 to 0.9 g/kg was administered to Rhesus monkeys. The animals were observed daily for various clinical signs and symptoms. They were weighed weekly, blood and urine was collected and examined every three months. After 52 weeks, the animals were sacrificed and an autopsy was performed.

Three animals belonging to the 0.90 g/kg group, two in the 0.30 g/kg group and one in the 0.10 g/kg died during the study. These deaths were considered to be related to ursodiol. Liver toxicity (small round-cell infiltration, vacuolar degeneration, necrosis of hepatic cells, phagocytosis and hepatic abscess) and thickening of the alveolar wall of the lungs was observed in deceased animals from all groups. Necrosis of the stomach wall was observed in deceased animals from the 0.90 g/kg group. A regression of body weight gain was seen in the 0.30 and 0.90 g/kg groups. Episodes of diarrhea were observed in all groups including the control group. No remarkable changes were noted in hematological, urinary, electrographic, blood pressure and ocular fundi examinations. However, serum SGPT, AST and ALP increased significantly.

From the above findings, it was concluded that ursodiol, when administered at daily doses exceeding 0.10 g/kg, caused hepatotoxicity in Rhesus monkeys.

Carcinogenicity

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.

Mutagenicity

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.

Reproduction and Teratology

Ursodiol did not show any teratogenic effect in mice, rats and rabbits at oral dose levels up to 1.5, 4.0 and 0.3 g/kg, respectively, and in mice and rats at intraperitoneal dose levels up to 0.2 g/kg. Furthermore, it did not influence mating performance and fertility, except in one study where these parameters were slightly reduced in female rats receiving 2.0 g/kg. Breeding capacity was not altered by the administration of ursodiol.

Oral administration of 1.5 g/kg in mice and 2.0 g/kg in rats induced a decrease in maternal weight gain and lower mean weights of live fetuses. In addition, the number of resorption sites was increased in rats at a dose of 2.0 g/kg. Rabbits were much more sensitive than mice and rats to the toxic action of ursodiol. The administration of doses of 0.1 g/kg and greater caused a decrease in food consumption, maternal body weight gain and motor activity as well as an increase in resorption sites, and absorption death.

Intraperitoneal administration of 0.2 g/kg ursodiol to mice and rats induced a decrease in maternal body weight gain, low fetal weight and an increase of resorption sites.

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45. 44. A single-dose (1x500 mg), crossover study to evaluate the comparative bioavailability between Novo-Ursodiol (ursodiol) 500 mg Tablets (Novopharm Limited) and URSO DS^TM (ursodiol) 500 mg Tablets (Axcan Pharma Inc., Canada) in 53 healthy, non-smoking, male and female subjects under fasting conditions. Data is on file at Novopharm Limited.