Urso

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. In addition to the replacement and displacement of toxic bile acids, other mechanisms of action include cytoprotection of the injured bile duct epithelial cells (cholangiocytes) against toxic effects of bile acids, inhibition of apotosis of hepatocytes, immunomodulatory effects, and stimulation of bile secretion by hepatocytes and cholangiocytes.

Pharmacodynamics

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.

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. Once absorbed, ursodiol undergoes hepatic extraction to the extent of about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, ursodiol is conjugated with glycine or taurine, then secreted into bile. These conjugates of ursodiol are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some ursodiol is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. In healthy subjects, at least 70% of ursodiol (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated ursodiol to plasma protein in healthy subjects or PBC patients. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1% except in severe cholestatic liver disease. During chronic administration of ursodiol, it becomes a major biliary and plasma bile acid. At a chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.

Clinical Studies

A U.S., multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of ursodeoxycholic acid at a dose of 13 to 15 mg/kg/day, administered in 3 or 4 divided doses in 180 patients with PBC (78% received four times a day dosage). Upon completion of the double-blind portion, all patients entered an open-label active treatment extension phase.

Treatment failure, the main efficacy 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 (p < 0.01) reduced in the URSO 250 mg group (20 of 86 (23%)) as compared to the placebo group (40 of 86 (47%)). Time to treatment failure, which excluded doubling of serum bilirubin and voluntary withdrawal, was also significantly (p < 0.001) delayed in the URSO 250 treated group (n=86, 803.8±24.9 d vs. 641.1±24.4 d for the placebo group (n=86) on average) regardless of either histologic stage or baseline bilirubin levels ( > 1.8 or ≤ 1.8 mg/dl).

Using a definition of treatment failure, which excluded doubling of serum bilirubin and voluntary withdrawal, time to treatment failure was significantly delayed in the URSO 250 group. In comparison with placebo, treatment with URSO 250 resulted in a significant improvement in the following serum hepatic biochemistries when compared to baseline: total bilirubin, SGOT, alkaline phosphatase and IgM.

A second study conducted in Canada randomized 222 PBC patients to ursodiol, 14 mg/kg/day or placebo, administered as a once daily dose in a double-blind manner during a two-year period. At two years, a statistically significant (p < 0.001) difference between the two treatments (n=106 for the URSO 250 group and n=106 for the placebo group), in favor of ursodiol, was demonstrated in the following: reduction in the proportion of patients exhibiting a more than 50% increase in serum bilirubin; median percent decrease in bilirubin (-17.12% for the URSO 250 group vs. +20.00% for the placebo group), transaminases (-40.54% for the URSO 250 group vs. +5.71% for the placebo group) and alkaline phosphatase (-47.61% for the URSO 250 group vs. -5.69% for the placebo group); 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 (n=10 withdrew from the URSO 250 group vs. n=15 from the placebo group) 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.

A randomized, two-period crossover study in fifty PBC patients compared efficacy of URSO 250 (ursodiol) in twice a day versus four times a day divided dosing schedules in 50 patients for 6 months in each crossover period. Mean percent changes from baseline in liver test results and Mayo risk score (n=46) and serum enrichment with UDCA (n=34) were not statistically significant with any dosage at any time interval. This study demonstrated that UDCA (13 to 15 mg/kg/day) given twice a day is equally effective to UDCA given four times a day. In addition, URSO 250 was given as a single versus three times a day dosing schedules in 10 patients. Due to the small number of patients in this arm of the study, it was not possible to conduct statistical comparisons between these regimens.

Appropriate Treatments

Patients with the following conditions should be instructed to receive appropriate management measures: variceal bleeding, hepatic encephalopathy, ascites, in need of an urgent liver transplant or hepatic function deterioration [see WARNINGS AND PRECAUTIONS].

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

Drug Interactions

Patients should be informed that absorption of URSO 250 and URSO Forte may be reduced if they are taking bile acid sequestering agents, such as cholestyramine and colestipol, aluminum-based antacids, or drugs known to alter the metabolism of cholesterol [see DRUG INTERACTIONS].

Avoid using antacids without your doctor's advice. Use only the specific type of antacid your doctor recommends. Antacids contain different medicines and some types can make it harder for your body to absorb ursodiol.

In the U.S.

• Actigall
• Urso
• Urso 250
• Urso Forte

Available Dosage Forms:

• Tablet
• Capsule

Therapeutic Class: Gastrointestinal Agent

Pharmacologic Class: Bile Acid

Ursodiol is used to dissolve gallstones in patients who do not need to have their gallbladders removed or in those in whom surgery should be avoided because of other medical problems. However, ursodiol works only in those patients whose gallstones are made of cholesterol and works best when these stones are small and of the “floating” type. It is also used to help prevent gallstones in patients who are on rapid weight-loss programs.

Ursodiol is also used to treat primary biliary cirrhosis (PBC). PBC is an autoimmune disorder that causes a patient's liver to have problems and not work properly.

This medicine is available only with your doctor's prescription.

Urso 250® and Urso Forte® (Ursodiol) tablets are indicated for the treatment of patients with primary biliary cirrhosis (PBC).

Bile Acid Sequestering Agents

Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of Urso 250 and Urso Forte by reducing its absorption.

Aluminum-based Antacids

Aluminum-based antacids have been shown to adsorb bile acids in vitro and may be expected to interfere with Urso 250 and Urso Forte in the same manner as the bile acid sequestering agents.

Drugs Affecting Lipid Metabolism

Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion and encourage cholesterol gallstone formation and hence may counteract the effectiveness of Urso 250 and Urso Forte.

Pregnancy

Pregnancy Category B. Reproduction studies have been performed in pregnant rats at oral doses up to 22 times the recommended maximum human dose (based on body surface area) and in pregnant rabbits at oral doses up to 7 times the recommended maximum human dose (based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to Ursodiol.

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether Ursodiol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Urso 250 and Urso Forte are administered to a nursing mother.

Pediatric Use

The safety and effectiveness of Urso 250 and Urso Forte in pediatric patients have not been established.

Applies to ursodiol: oral capsule, oral tablet

Along with its needed effects, ursodiol (the active ingredient contained in Urso) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ursodiol:

• Bladder pain
• bloody or cloudy urine
• difficult, burning, or painful urination
• dizziness
• fast heartbeat
• frequent urge to urinate
• indigestion
• lower back or side pain
• severe nausea
• skin rash or itching over the entire body
• stomach pain
• vomiting
• weakness

• Black, tarry stools
• chest pain
• chills or fever
• cough
• pinpoint red spots on the skin
• severe or continuing stomach pain
• sore throat or swollen glands
• sores, ulcers, or white spots on the lips or in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

• Clay-colored stools
• dark urine
• difficulty with swallowing
• headache
• hives or welts
• hoarseness
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• nausea
• redness of the skin
• slow or irregular breathing
• tightness in the chest
• unpleasant breath odor
• yellow eyes or skin

Some side effects of ursodiol may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• body aches or pain
• congestion
• constipation
• general feeling of discomfort or illness
• heartburn
• loss of voice
• muscle aches
• muscle or bone pain
• pain, swelling, or redness in the joints
• runny nose
• sweating
• trouble sleeping

• Diarrhea

• Worsening psoriasis

• Acid or sour stomach
• belching bloating or swelling of face, arms, hands, lower legs, or feet
• difficulty with moving
• rapid weight gain
• stomach discomfort or upset
• tingling of the hands or feet
• unusual weight gain or loss

Applies to ursodiol: oral capsule, oral tablet

Gastrointestinal

Very common (10% or more): Abdominal pain (up to 43.2%), diarrhea (up to 27.1%), constipation (up to 26.4%), nausea (up to 17.4%), dyspepsia (up to 16.8%), vomiting (up to 13.7%)
Common (1% to 10%): Flatulence (up to 7.7%), cholecystitis (5.2%), gastrointestinal disorder (3.9%), esophagitis (1.7%), peptic ulcer (1.3%)
Postmarketing reports: Abdominal discomfort, abdominal pain, diarrhea, constipation, dyspepsia, nausea, vomiting[Ref]

Nervous system

Very common (10% or more): Headache (up to 24.8%), dizziness (16.5%)
Common (1% to 10%): Insomnia (1.9%)
Postmarketing reports: Dizziness, headache[Ref]

Other

Very common (10% or more): Viral infection (up to 19.4%)
Common (1% to 10%): Fatigue (up to 7.8%), influenza-like symptoms (6.5%), chest pain (3.2%), asthenia (1.7%)
Postmarketing reports: Malaise, peripheral edema, pyrexia[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 15.5%), sinusitis (up to 11%)
Common (1% to 10%): Pharyngitis (up to 8.4%), coughing (7.1%), bronchitis (6.5%), rhinitis (5.2%)
Postmarketing reports: Cough[Ref]

Musculoskeletal

Very common (10% or more): Back pain (up to 11.8%)
Common (1% to 10%): Arthralgia (7.7%), musculoskeletal pain (5.9%), arthritis (5.8%), myalgia (5.8%)
Postmarketing reports: Myalgia[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection (6.5%), dysmenorrhea (5.6%)[Ref]

Dermatologic

Common (1% to 10%): Alopecia (5.3%), skin rash (2.6%)
Postmarketing reports: Alopecia, pruritus, rash[Ref]

Hypersensitivity

Common (1% to 10%): Allergy (5.2%)
Postmarketing reports: Drug hypersensitivity (including facial edema, urticaria, angioedema, laryngeal edema)[Ref]

Hematologic

Common (1% to 10%): Leukopenia (2.6%), thrombocytopenia (1.3%)[Ref]

Metabolic

Common (1% to 10%): Anorexia (1.7%), elevated blood glucose (up to 1.3%)[Ref]

Renal

Common (1% to 10%): Elevated creatinine (1.3%)[Ref]

Hepatic

Postmarketing reports: Jaundice (or aggravation of preexisting jaundice), increased ALT, increased AST, increased blood alkaline phosphatase, increased blood bilirubin, increased gamma-glutamyltransferase, increased hepatic enzymes, abnormal liver function test, increased transaminases[Ref]

Some side effects of Urso may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.