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URSOFALK®
Axcan Pharma
Ursodiol
Litholytic Agent - Cholestatic Liver Diseases
 
Action And Clinical Pharmacology: Ursodiol, a naturally occurring bile acid, is present as a minor fraction of the total human bile acids. Oral administration of ursodiol increases this fraction in a dose related manner, to become the major biliary acid. Since in patients with gallstones, the total bile acid pool size is generally reduced, the exogenous supply of ursodiol helps to increase this bile acid pool size and increases the cholesterol saturation index. In addition, the fecal bile acid loss is increased and cholesterol secretion into the bile is reduced, without a concomitant reduction in phospholipids. Consequently, the cholesterol saturation of bile is reduced, allowing gradual solubilization of cholesterol from gallstones to occur.

The cholesterol-lowering effect observed following the administration of ursodiol in patients with primary biliary cirrhosis could be related to an improvement of cholestatis, 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.

Indications And Clinical Uses: Gallstone Dissolution: For the dissolution of gallstones and the treatment of associated symptoms in patients with radiolucent, noncalcified gallstones of less than 20 mm size in well opacifying gallbladders in whom cholecystectomy would be undertaken except: for patients who refuse surgery, for the presence of increased surgical risk due to systemic disease, advanced age and idiosyncratic reaction to general anesthesia.

Likelihood of therapeutic success with ursodiol is far greater if the stones are floatable or if the stone size is smaller since the dissolution rate is inversely proportional to the size of the stones. Safety of use of ursodiol beyond 24 months is not established.

Cholestatic Liver Diseases (PBC): Ursodiol is also 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 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 disease.

Therefore, liver function tests (g-GT, alkaline phosphatase, AST, ALT), and bilirubin level should be monitored: every month for 3 months after start of therapy, and then every 6 months. Serum levels of these parameters usually decrease rapidly thus demonstrating efficacy. Treatment should be discontinued if the levels of above parameters increase (see Precautions).

Ursodiol is not indicated for the treatment of decompensated cirrhosis.

The long-term effect of ursodiol treatment for chronic cholestatic liver disease conditions have not been fully established. Results from clinical trials indicate that ursodiol treatment improves certain laboratory parameters, such as bilirubin level, and serum levels of alkaline phosphatase, AST, and ALT and IgM. Ursodiol may be effective in slowing down the progression of the disease.

Contra-Indications: Patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis or biliary-gastrointestinal fistula, and in patients with calcified cholesterol stones, radiopaque stones or radiolucent bile pigment stones. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Gallstone Dissolution: Patients should be informed of the response rate, recurrence rate and the underlying cholecystectomy rate (4%) seen in patients while on the treatment.

Cholecystectomy as an alternative to therapy with ursodiol should be considered as it offers the advantages of immediate and permanent stone removal but carries a high risk in some patients.

Precautions: Gallstone Dissolution: Patient Monitoring: The following tests are important for patient monitoring: Liver Tests: Ursodiol therapy has not been associated with liver damage. Lithocholic acid, a naturally occurring bile acid, is known to be a liver-toxic metabolite of ursodiol. This bile acid is formed in the gut from ursodiol. Lithocholic acid is detoxified in the liver by sulfation and although man appears to be an efficient sulfater, it is possible that some patients may have a congenital or acquired deficiency in sulfation, thereby predisposing them to lithocholic acid-induced liver damage. For these reasons patients given ursodiol should have AST and ALT measured at the initiation of therapy, after 3 months of therapy and every 6 months thereafter. Therapy should be discontinued if increased levels persist.

Echogram: Recommended prior to treatment to determine the presence of gallbladder stones and gallbladder function, and at 6 month intervals during the first year of treatment to monitor stone dissolution; also recommended after gallstone dissolution to monitor for possible recurrence.

Cholecystogram: Prior to treatment to judge if the gallbladder is functional or not, and whether gallstones are translucent (mostly cholesterol stones) or radiopaque (calcified stones, pigment stones).

Patients should be counselled on the importance of periodic visits for liver function tests and oral radiograms or ultrasonograms for monitoring stone dissolution. They should be made aware of symptoms of gallstone complications and be warned to report immediately such symptoms to the physicians.

Patients should be instructed on ways to facilitate faithful compliance with the dosage regimen throughout the usual long-term therapy.

Cholestatic liver diseases (PBC): Patient Monitoring: 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 (g-GT, alkaline phosphatase, AST, ALT), and bilirubin level should be monitored: every month for 3 months after start of therapy, and then every 6 months. Serum levels of these parameters usually decrease rapidly thus demonstrating efficacy. Treatment should be discontinued if the levels of above parameters increase.

Drug Interactions: Bile acid sequestrants such as cholestyramine or colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum based antacids have been shown to absorb bile acid in vitro and may be expected to interfere with ursodiol in the same manner as the sequestering agents. Estrogens, oral contraceptives and fibrates increase biliary cholesterol secretion and hence may counteract the effectiveness of ursodiol. Statins have been shown to induce a decrease of the cholesterol saturation index as a consequence of a depression of the biliary cholesterol secretion rate, which potentiates the similar effect of ursodiol, but does not seem to have an effect on gallstone dissolution.

Carcinogenesis, Mutagenesis and Impairment of Fertility: Ursodiol has no carcinogenic, mutagenic or teratogenic effects in laboratory animals treated at higher doses than those intended for therapy in human and after long-term treatment.

Pregnancy: 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 appraised of the potential hazard to the fetus. To date, no reports of adverse reactions have been filed. In pilot studies, ursodiol has been effectively used for the treatment of cholestatis of pregnancy during the last trimester without any side effects.

Lactation: It is not known whether ursodiol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ursodiol is administered to a nursing mother.

Children: The safety and effectiveness of ursodiol in children has 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.

Miscellaneous: Risk-benefit should be considered in the case of gallstone complications such as biliary gastrointestinal fistula, biliary obstruction, cholecystitis and pancreatitis.

Adverse Reactions: Gallstone Dissolution: The following adverse reactions have been reported with the use of ursodiol in very rare cases: exacerbation of pre-existing psoriasis, rash, urticaria, dry skin, sweating, hair thinning, biliary pain, cholecystitis, constipation, stomatitis, flatulence, headache, fatigue, anxiety, depression, sleep disorder, arthralgia, myalgia, back pain, cough and rhinitis.

In various clinical trials in gallstone dissolution, 648 patients were treated with ursodiol. Six of 648 (1.0%) had gastrointestinal complaints: 4 had diarrhea (0.6%) and 2 dyspepsia (0.3%). In addition, 1 patient was thought to have pruritus, 1 foot swelling and 4 other miscellaneous complaints.

Cholestatic Liver Diseases (PBC): Five hundred and forty eight patients (275 ursodiol, 273 placebo) have been enrolled in the three main clinical trials in primary biliary cirrhosis. Only one patient on ursodiol complained that preexisting pruritus became aggravated and severe 1 hour after administration of the drug. Treatment was discontinued and cholestyramine was administered to restore the patient to her original condition.

The following symptoms were also reported by one patient in the ursodiol group: abdominal pain with postprandial distension, pruritus, dizziness, temporal pressure, in the third month of treatment, for 15 days. The symptoms disappeared despite continuation of treatment, thus making the causal relationship to the drug doubtful.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Accidental or intentional overdosage of ursodiol has not been reported and likely would result only in self-limiting acute diarrhea which should be treated symptomatically. tag_DosageDosage

Dosage And Administration: Gallstone Dissolution: The recommended dose is 8 to 10 mg/kg/day which may be given in 2 divided doses, 1 capsule in the morning with breakfast and 2 to 3 capsules at bedtime with food.

Table I may be consulted to calculate the quantity of capsules to be taken per day. An incremental program of increasing dosage has not usually been employed. Dosage less than 8 mg/kg/day is relatively ineffective and is not recommended.

Ultrasound images of the gallbladder should be obtained at 6 month intervals for the first year of therapy to monitor gallstone response. If gallstones appear to have dissolved, ursodiol therapy should be continued another 3 months, and dissolution confirmed on a repeated ultrasound examination. Most patients who eventually achieve complete stone dissolution will show partial or complete dissolution at first treatment re-evaluation. If partial stone dissolution is not seen by 12 months of ursodiol therapy, the likelihood of success is greatly reduced, and therapy should be stopped.

Cholestatic Liver Diseases (PBC): The recommended dose is 13 to 15 mg/kg/day which may be given in 2 divided doses, i.e. in the morning and at bedtime, with food.

Patient Monitoring: Liver function tests (g-GT, alkaline phosphatase, AST, ALT), and bilirubin level should be monitored: every month for 3 months after start of therapy, and then every 6 months. Serum levels of these parameters usually decrease rapidly thus demonstrating efficacy. Treatment should be discontinued if the levels of above parameters increase.



Availability And Storage: Each opaque, white, gelatin capsule, contains: ursodiol 250 mg. Nonmedicinal ingredients: cornstarch, colloidal silicon dioxide, gelatin, magnesium stearate, polysorbate, salt and titanium dioxide. High density polyethylene bottles of 100. Store at room temperature.