Table of Contents
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SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 10 ACTION AND CLINICAL PHARMACOLOGY 11 STORAGE AND STABILITY 12 SPECIAL HANDLING INSTRUCTIONS 12 DOSAGE FORMS, COMPOSITION AND PACKAGING 12
PHARMACEUTICAL INFORMATION 14 CLINICAL TRIALS 15 DETAILED PHARMACOLOGY 17 TOXICOLOGY 18 REFERENCES 20
URSO(r) and URSO DS(tm) Tablets
Axcan Pharma Inc. Page 2 of 27
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| oral | tablet 250 mg, 500 mg | None |
URSO(r) and URSO DS(tm) (ursodiol, also known as ursodeoxycholic acid (UDCA)) are 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, g-GT, bilirubin), and also an increase in IgM levels and the presence of antimitochondrial antibodies in PBC. The monitoring of the efficacy of URSO(r) and URSO DS(tm) 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. Therefore, liver function tests (g-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, thus, demonstrating efficacy. Treatment should be discontinued if the levels of the above parameters increase (see WARNINGS and PRECAUTIONS). URSO(r) and URSO DS(tm) are not indicated for the treatment of decompensated cirrhosis.
Geriatrics:
Appropriate studies with URSO(r) and URSO DS(tm) have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of URSO(r) and URSO DS(tm) in the elderly are not expected.
Pediatrics:
The safety and effectiveness of URSO(r) and URSO DS(tm) in children have not been established.
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.
Carcinogenesis and Mutagenesis
URSO(r) and URSO DS(tm) 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 (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, URSO(r) and URSO DS(tm) 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 URSO(r) or URSO DS(tm) is administered to a nursing mother. Pediatrics: The safety and effectiveness of URSO(r) and URSO DS(tm) in children have not been established. Geriatrics: Appropriate studies with URSO(r) and URSO DS(tm) have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of URSO(r) and URSO DS(tm) in the elderly are not expected.
Monitoring and Laboratory Tests
Lithocholic acid, one of the metabolites of ursodeoxycholic acid (URSO(r) and URSO DS(tm)) is hepatotoxic unless it is effectively detoxified in the liver. Therefore, the following tests are important for patient monitoring: Liver function tests (g-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.
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 URSO(r) 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 URSO(r) 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
| Adverse event (ordered by MedDRA System Organ Class) | Visit at 12 Months | Visit at 24 Months | |||
| UDCA 1 n (%) | Placebo n (%) | UDCA 1 n (%) | Placebo n (%) | ||
| Blood and lymphatic system disorders | Leukopenia | - | - | 2 (2.63) | - |
| Gastrointestinal disorders | Diarrhea | - | - | 1 (1.32) | - |
| Peptic ulcer | - | - | 1 (1.32) | - | |
| Adverse event (ordered by MedDRA System Organ Class) | Visit at 12 Months | Visit at 24 Months | |||
| UDCA 1 n (%) | Placebo n (%) | UDCA 1 n (%) | Placebo n (%) | ||
| Investigations | Blood creatinine increased | - | - | 1 (1.32) | - |
| Blood glucose increased | 1 (1.18) | - | 1 (1.32) | - | |
| Skin and subcutaneous tissue disorders | Rash | - | - | 2 (2.63) | - |
UDCA=Ursodeoxycholic acid=Ursodiol =URSO(r)
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
| Adverse event (ordered by MedDRA System Organ Class) | TEAEs, n (%) | |
| Blood and lymphatic system disorders | Anemia | 1 (1.7) |
| Lymphadenopathy | 2 (3.3) | |
| Cardiac disorders | Arrhythmia | 2 (3.3) |
| Cardiovascular disorder | 2 (3.3) | |
| Ear and labyrinth disorders | Deafness | 1 (1.7) |
| Vertigo | 1 (1.7) | |
| Eye disorders | Cataract | 2 (3.3) |
| Eye disorder | 1 (1.7) | |
| Retinal disorder | 1 (1.7) | |
| Gastrointestinal disorders | Abdominal pain | 2 (3.3) |
| Diarrhea | 2 (3.3) | |
| Dyspepsia | 6 (10) | |
| Dysphagia | 1 (1.7) | |
| Esophagitis | 1 (1.7) | |
| Flatulence | 1 (1.7) | |
| Gastrointestinal disorder | 3 (5.0) | |
| Nausea | 5 (8.3) | |
| Salivary gland enlargement | 1 (1.7) | |
| Stomach ulcer | 1 (1.7) | |
| General disorders and | Asthenia | 7 (11.7) |
| Adverse event (ordered by MedDRA System Organ Class) | TEAEs, n (%) | |
| administration site conditions | Chest pain | 3 (5.0) |
| Chest pain substernal | 1 (1.7) | |
| Cyst | 1 (1.7) | |
| Edema | 5 (8.3) | |
| Edema generalized | 1 (1.7) | |
| Edema peripheral | 5 (8.3) | |
| Granuloma | 1 (1.7) | |
| Hemorrhagic ulcer | 1 (1.7) | |
| Pain | 1 (1.7) | |
| Hepatobiliary disorders | Biliary pain | 1 (1.7) |
| Immune system disorders | Amyloidosis | 1 (1.7) |
| Infections and infestations | Bronchitis | 1 (1.7) |
| Cystitis | 1 (1.7) | |
| Herpes simplex | 1 (1.7) | |
| Infection | 1 (1.7) | |
| Otitis media | 1 (1.7) | |
| Pharyngitis | 1 (1.7) | |
| Pneumonia | 1 (1.7) | |
| Rhinitis | 2 (3.3) | |
| Urinary tract infection | 1 (1.7) | |
| Vaginitis | 1 (1.7) | |
| Metabolism and nutrition disorders | Anorexia | 1 (1.7) |
| Diabetes mellitus | 2 (3.3) | |
| Musculoskeletal and connective tissue disorders | Back pain | 1 (1.7) |
| Bone disorder | 1 (1.7) | |
| Bone fracture spontaneous | 1 (1.7) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Breast neoplasm | 1 (1.7) |
| Lung nodule | 1 (1.7) | |
| Plantar warts | 1 (1.7) | |
| Nervous system disorders | Dizziness | 2 (3.3) |
| Headache | 1 (1.7) | |
| Migraine | 1 (1.7) | |
| Paresthesia | 1 (1.7) | |
| Reproductive system and breast disorders | Breast nodule | 1 (1.7) |
| Fibrocystic breast disease | 2 (3.3) | |
| Menorrhagia | 1 (1.7) | |
| Respiratory, thoracic and mediastinal disorders | Dyspnea | 1 (1.7) |
| Lung disorder | 1 (1.7) | |
| Respiratory disorder | 1 (1.7) | |
| Sore nose | 2 (3.3) | |
| Skin and subcutaneous tissue disorders | Acne | 2 (3.3) |
| Miliaria | 1 (1,7) | |
| Pruritus | 3 (5.0) | |
| Psoriasis | 1 (1.7) | |
| Rash | 1 (1.7) | |
| Skin disorder | 2 (3.3) | |
| Skin hypertrophy | 1 (1.7) | |
| Vascular disorders | Hypertension | 5 (8.3) |
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
| Baseline | Endpoint | Change from Baseline | |||||
| UDCA | Placebo | UDCA | Placebo | UDCA ( +- SD) | Placebo ( +- SD) | ||
| WBC | Mean | 5.9 | 6.2 | 5.5 | 5.8 | -0.5 * * | -0.5 |
| ( +- SD) | (2.0) | (4.1) | (1.6) | (2.4) | (1.4) | (4.3) | |
| n | 88 | 87 | 83 | 75 | |||
| Platelets | Mean | 238.5 | 245.4 | 211.2 | 223.9 | -29.4 * * | -17.7 * |
| ( +- SD) | (92.5) | (112.4) | (87.2) | (94.3) | (39.3) | (58.0) | |
| n | 86 | 86 | 82 | 74 | |||
* Statistically different from zero, p < 0.05
* *Statistically different from zero, p < 0.01
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
| Baseline | Endpoint | Change from Baseline | |||||
| UDCA | Placebo | UDCA | Placebo | UDCA ( +- SD) | Placebo ( +- SD) | ||
| Calcium | Mean | 9.49 a | 9.47 | 9.39 | 9.30 | -0.12 * * ,a | -0.19 * * |
| (mg/dL) | ( +- SD) | (0.40) | (0.40) | (0.43) | (0.51) | (0.37) | (0.37) |
| n | 89 | 91 | 83 | 76 | |||
| Cholesterol | Mean | 287.73 a | 276.03 | 223.53 | 261.46 | -67.39 * * ,b | -11.32 * |
| (mg/dL) | ( +- SD) | (121.12) | (105.22) | (56.80) | (83.53) | (93.31) | (47.70) |
| n | 89 | 91 | 83 | 76 | |||
| Creatinine | Mean | 0.86 | 0.84 | 0.92 | 0.92 | 0.07 * * a | 0.07 * * |
| (mg/dL) | ( +- SD) | (0.19) | (0.21) | (0.19) | (0.26) | (0.18) | (0.23) |
| n | 89 | 91 | 83 | 76 | |||
| Total | Mean | 8.66 a | 8.60 | 7.96 | 8.27 | -0.69 * ,a | -0.49 |
| Thyroxine | ( +- SD) | (1.63) | (2.27) | (1.87) | (3.25) | (1.52) | (2.52) |
| ( u g/dL) | n | 87 | 90 | 83 | 74 | ||
| Baseline | Endpoint | Change from Baseline | |||||
| UDCA | Placebo | UDCA | Placebo | UDCA ( +- SD) | Placebo ( +- SD) | ||
| Triglycerides | Mean | 102.82 a | 117.11 | 114.18 | 121.52 | 11.76 * ,a | 3.00 |
| (mg/dL) | ( +- SD) | (49.25) | (70.57) | (55.13) | (57.56) | (44.38) | (56.74) |
| n | 88 | 89 | 83 | 75 | |||
* * Statistically different from zero, p < 0.01
* Statistically different from zero, p < 0.05
a
p = ns, UDCA versus placebo
b
p = 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 (URSO(r)). 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(r) 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.
Overview
Bile acid sequestering agents may interfere with the action of URSO(r) and URSO DS(tm) 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(r) and URSO DS(tm). 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
| Effect | Clinical comment | |
| Bile acid sequestrants (i.e. cholestyramine or cholestipol) | Reduces ursodiol absorption | May interfere with the action of URSO (r) and URSO DS(tm) |
| Aluminum based antacids | Reduces ursodiol absorption Adsorbs bile acid in vitro | May be expected to interfere with URSO (r) and URSO DS(tm) |
| Cytochrome P4503A substrates cyclosporine, nitrendipine and dapsone | Metabolic interaction. | Metabolic interactions with compounds metabolized by cytochrome P4503A are to be expected. |
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.
Dosing Considerations
Liver function tests (g-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 URSO(r) and URSO DS(tm) (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.
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.
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 URSO(r) and URSO DS(tm) 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(r) and URSO DS(tm) 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
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.
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.
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.
Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1%, except in severe cholestatic liver disease.
URSO(r) and URSO DS(tm) tablets should be stored at controlled room temperature (15deg - 30degC) in a closed container.
There are no special handling instructions.
URSO(r) (ursodiol) is available in a strength of 250 mg as a white, elliptical, biconvex, film- coated tablet, engraved with "URS785" on one side. Each bottle contains 100 tablets.
URSO DS(tm) (ursodiol) is available in a strength of 500 mg as a white, elliptical, biconvex, film- coated tablet, engraved with "URS790" on one side. Each bottle contains 100 tablets. In addition to ursodiol as the active ingredient, URSO(r) and URSO DS(tm) contain the following excipients: 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.