NRA-Ursodiol Product Monograph

RECENT MAJOR LABEL CHANGES

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TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .................................................................................................................... 4

1.1 Pediatrics............................................................................................................................ 4 1.2 Geriatrics ............................................................................................................................ 4 2 CONTRAINDICATIONS ....................................................................................................... 4 4 DOSAGE AND ADMINISTRATION ....................................................................................... 4

4.1 Dosing Considerations ....................................................................................................... 4 4.2 Recommended Dose and Dosage Adjustment .................................................................. 5 4.3 Administration ................................................................................................................... 5 4.4 Missed Dose ....................................................................................................................... 5 5 OVERDOSAGE ................................................................................................................... 5 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING........................................ 5 7 WARNINGS AND PRECAUTIONS ........................................................................................ 6

7.1 Special Populations ............................................................................................................ 7 7.1.1 Pregnant Women ............................................................................................................ 7 7.1.2 Breast-feeding ................................................................................................................. 7 7.1.3 Pediatrics ........................................................................................................................ 7 7.1.4 Geriatrics ......................................................................................................................... 7 8 ADVERSE REACTIONS ........................................................................................................ 7

8.1 Adverse Reaction Overview ............................................................................................... 7 8.2 Clinical Trial Adverse Reactions ......................................................................................... 7 8.3 Less Common Clinical Trial Adverse Reactions (<1%)...................................................... 10 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................................................ 11 8.5 Post-Market Adverse Reactions ...................................................................................... 12 9 DRUG INTERACTIONS ..................................................................................................... 12

9.2 Drug Interactions Overview ............................................................................................. 12 9.3 Drug-Behavioural Interactions ......................................................................................... 13 9.4 Drug-Drug Interactions .................................................................................................... 13 9.5 Drug-Food Interactions .................................................................................................... 13 9.6 Drug-Herb Interactions .................................................................................................... 13 9.7 Drug-Laboratory Test Interactions .................................................................................. 13 10 CLINICAL PHARMACOLOGY ........................................................................................... 13

10.1 Mechanism of Action ..................................................................................................... 13

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10.2 Pharmacodynamics ........................................................................................................ 14 10.3 Pharmacokinetics ........................................................................................................... 14 11 STORAGE, STABILITY AND DISPOSAL ............................................................................. 15 12 SPECIAL HANDLING INSTRUCTIONS ............................................................................... 15 PART II: SCIENTIFIC INFORMATION ...................................................................................... 16 13 PHARMACEUTICAL INFORMATION ................................................................................ 16 14 CLINICAL TRIALS............................................................................................................ 17

14.1 Clinical Trials by Indication ............................................................................................ 17 Primary Biliary Cirrhosis (PBC) ............................................................................................... 17 14.2 Comparative Bioavailability Studies .............................................................................. 20 15 MICROBIOLOGY ............................................................................................................ 20 16 NON-CLINICAL TOXICOLOGY ......................................................................................... 20 17 SUPPORTING PRODUCT MONOGRAPHS ........................................................................ 23

PATIENT MEDICATION INFORMATION ................................................................................. 24

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PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

NRA-Ursodiol (ursodiol tablets), also known as ursodeoxycholic acid (UDCA) are indicated for:

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

1.1 Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2 CONTRAINDICATIONS

NRA-Ursodiol are contraindicated in patients:

• who are hypersensitive to ursodiol or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph.
• with complete biliary obstruction of extrahepatic origin;
• with widespread intrahepatic obstruction

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The monitoring of NRA-Ursodiol in the management of cholestatic liver diseases should be based on the biochemical parameters of cholestasis 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.

Patient Monitoring: Serum 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. Serial monitoring will allow for the early detection of a possible deterioration of the hepatic function. Serum levels of these parameters usually decrease rapidly. Improved serum liver tests (e.g. AST, ALT) do not always correlate with improved disease status. For patients who have a recent history of adequate biochemical response to the treatment, UDCA discontinuation should be considered when serum liver function tests increase to a level considered clinically significant. See 7 WARNINGS AND PRECAUTIONS.

Caution has to be exercised to maintain the bile flow of the patients taking UDCA.

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4.2 Recommended Dose and Dosage Adjustment

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

Health Canada has not authorized an indication for pediatric use.

4.3 Administration

The NRA-Ursodiol 500 mg scored tablet can be broken in halves to provide recommended dosage.

4.4 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.

5 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

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250 mg tablet:

NRA-Ursodiol, 250 mg is available as white to off-white, oval shaped, film-coated tablet debossed with “G72” on one side & “250” on the other side. Available in bottles of 100 and 500 tablets.

500 mg tablet:

NRA-Ursodiol, 500 mg is available as white to off-white, oval shaped film-coated tablet plain with score line on one side and debossed with ‘U11’ on the other side. Available in bottles of 100 and 500 tablets.

7 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 16 NON-CLINICAL TOXICOLOGY).

Gastrointestinal

Bezoars in Patients with Risk for Intestinal Stenosis or Stasis

There have been very rare post-marketing reports of bezoars leading to obstructive symptoms that require surgical interventions in ursodiol-treated patients with medical conditions that predispose to intestinal stenosis or stasis (e.g. surgical enteroanastomoses, Crohn's disease).

Hepatic/Biliary/Pancreatic

Patients with variceal bleeding, hepatic encephalopathy, ascites, or in need of an urgent liver transplant, should receive appropriate specific treatment. Caution should be exercised when UDCA is administered in a setting of partial biliary obstruction of extra-hepatic origin.

Monitoring and Laboratory Tests

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

Serum 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. Serial monitoring will allow for the early detection of a possible deterioration of the hepatic function. Serum levels of these parameters usually decrease rapidly. Improved serum liver tests (e.g. AST, ALT) do not always correlate with improved disease status. For patients who have a recent history of adequate biochemical response to the treatment, UDCA discontinuation should be considered when serum liver function tests increase to a level considered clinically significant See 4 DOSAGE AND ADMINISTRATION.

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Caution has to be exercised to maintain the bile flow of the patients taking UDCA.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, NRA-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 fetus. See also 16 NON-CLINICAL TOXICOLOGY.

7.1.2 Breast-feeding

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

7.1.3 Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

8 ADVERSE REACTIONS

8.1 Adverse 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.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in

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real-world use.

The adverse reactions in Table 2 below were observed in clinical trials in primary biliary cirrhosis with 180 patients (89 randomized to ursodiol tablets 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 tablets group, and that are higher than placebo are included in Table 2. 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 2: Adverse Events with a Frequency ≥ 1% Observed in a Clinical Trial of 180 Patients

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.

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Table 3: Treatment-Emergent Adverse Events (TEAEs) with a Frequency of ≥ 1 %

Observed in a Clinical Trial of 60 PBC patients

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

Analysis of the data in the trial with 180 patients (Table 2) 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 3) are available due to the small sample size.

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8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial 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 Table 4 and Table 5.

Table 4: 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 hemoglobin.

Table 5: Clinical Chemistries: Changes from Baseline

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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.

8.5 Post-Market Adverse Reactions

The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post-approval use of ursodiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: eosinophilia, neutropenia, thrombocytopenia.

Cardiac disorders: palpitations.

Gastrointestinal disorders: abdominal discomfort, bezoars, cheilitis, constipation, vomiting.

General disorders and administration site conditions: malaise, pyrexia.

Hepatobiliary disorders: jaundice (or aggravation of pre-existing jaundice)

Immune system disorders: angioedema and laryngeal edema, drug hypersensitivity to include facial edema, urticaria.

Investigations: blood urine present, weight decreased, weight increased, ALT increased, AST increased, blood alkaline phosphatase increased, blood bilirubin increased, γ-GT increased, transaminases increased. Rare instances of severe liver injury (elevated values for ALT/AST, ALP, γ-GTP and total bilirubin) have been reported with ursodiol tablets.

Musculoskeletal and connective tissue disorders: myalgia

Respiratory, thoracic and mediastinal disorders: cough, interstitial lung disease.

Skin and subcutaneous tissue disorder: alopecia, dermatitis exfoliative, drug eruption, erythema, lichenoid keratosis, photosensitivity reaction.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

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

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9.3 Drug-Behavioural Interactions

Interactions with behaviour have not been established.

9.4 Drug-Drug Interactions

Table 6: Established or Potential Drug-Drug Interactions

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 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 apoptosis 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.

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The cholesterol-lowering effect observed following the administration of ursodiol tablets 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 tablets might be the common denominator of these two mechanisms.

10.2 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.

10.3 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

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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.

Elimination

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

11 STORAGE, STABILITY AND DISPOSAL

NRA-Ursodiol, 250 mg and 500 mg should be stored in a closed container between 15°C to 30°C.

Half-tablets (scored NRA-Ursodiol, 500 mg broken in half) maintain acceptable quality for up to 28 days when stored in the current packaging (bottles) at 15°C to 30°C.

12 SPECIAL HANDLING INSTRUCTIONS

To prevent leakage of the active medicinal ingredient (ursodiol) from the cut tablets onto the surface of whole tablets and spreading the bitter taste, it is recommended that cut tablets be stored separately from whole tablets.

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PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ursodiol

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

Molecular formula and molecular mass: C₂₄H₄₀O₄ 392.57 g/mol

Structural formula:

Physicochemical properties:

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

Solubility: Very slightly soluble in water, freely soluble in alcohol, slightly soluble in acetone and in methylene chloride.

Melting Range: 200°C - 205°C

pKa: 6.0

pH: Alkaline

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14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Primary Biliary Cirrhosis (PBC)

Table 7 - Summary of patient demographics for clinical trials in primary biliary cirrhosis

(PBC)

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.

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. 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.

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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 mcmol/L) or the occurrence of severe complications (ascites or variceal bleeding) or an adverse event.

Study Results

Table 8: Primary Efficacy Analysis for clinical trials in primary biliary cirrhosis (PBC) –

US and Canadian Studies

Table 9: Primary Efficacy Analysis for clinical trials in primary biliary cirrhosis (PBC) –

Multinational Study

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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.

Table 10 – Combined Analysis for clinical trials in primary biliary cirrhosis (PBC)

Unapproved High-Dose Ursodeoxycholic Acid for the Treatment of Primary Sclerosing Cholangitis:

In a recent Clinical Trial, one hundred fifty adult patients with primary sclerosing cholangitis (PSC) were enrolled in a long-term, randomized, double-blind controlled trial of high-dose (28-30 mg/kg/day – 1.5 to 2.0 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. 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 in PSC

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did not improve survival and was associated with higher rates of serious adverse events.

14.2 Comparative Bioavailability Studies

A double-blind, randomized, two-treatment, two-sequence, two-period, single oral dose, two-way crossover comparative bioavailability study of NRA-Ursodiol, 2 x 250 mg manufactured by Nora Pharma Inc. versus URSO^® (ursodiol) Tablets, 2 x 250 mg by Axcan Pharma Inc., Canada, was conducted in 23 healthy male subjects under fasting conditions. The bioavailability data were measured and the results are summarized in the following table:

¹ NRA-Ursodiol (ursodiol) 2 x 250 mg tablets (Nora Pharma Inc)

² URSO^® (ursodiol) 2 x 250 mg tablets by Axcan Pharma Inc., Canada, was purchased in Canada.

³ Due to the nature of the active ingredient, a meaningful estimate of the AUC_I and T_1/2 parameters could not be derived and are therefore not reported

⁴ T=72 hours

⁵ Expressed as the median (range) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Acute Toxicity

Results from various studies indicated that oral, subcutaneous, intraperitoneal and intravenous

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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.

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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.

^PrNRA-Ursodiol (Ursodiol Tablets USP, 250 mg and 500 mg) Page 23 of 28

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.

Reproductive and Developmental Toxicology:

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.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. Product Monograph: ^PrGLN-Ursodiol (Ursodiol Tablets, 250 mg and 500 mg) by Glenmark Pharmaceuticals Canada Inc. Date of Revision: September 21, 2023, Control #245047.