URSODIOL (Generic for RELTONE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer ursodiol orally with food or milk; infants may receive ursodiol with milk, formula, or soft food.
Oral Solid Formulations
-Ursodiol 500 mg tablets (URSO Forte) are scored tablets that can be broken in half to provide the recommended dosage.
-Once split in half, the tablet segments should be washed down with water; the broken tablets should not be chewed or kept in the mouth for a very long period of time as a bitter taste can occur. Do not use if the tablet is not broken correctly
-Half-tablets maintain acceptable quality for up to 28 days when stored in the provided packaging (bottles) at 20 to 25 degrees C (68 to 77 degrees F). Because of the bitter taste, the tablet halves should be stored separately from the whole tablets.

Extemporaneous Compounding-Oral
-Shake well before use. Administer using a calibrated oral syringe or dosage cup.

Extemporaneous preparation of oral suspensions:
-To prepare a 25 mg/ml suspension: Open ten 300-mg ursodiol capsules into a glass mortar and mix capsule contents with 10 ml Glycerin, USP until a smooth mixture is obtained. Add 60 ml Ora-Plus in proportions and continue to levigate until a smooth mixture is achieved. Transfer mixture to a light-resistant bottle; add a small amount of Orange Syrup, NF to wash remaining drug from the mortar to bottle. Add additional syrup to make a final volume of 120 ml. Label 'shake well'. The suspension is stable for 60 days at room temperature or refrigerated.
-To prepare a 60 mg/ml suspension: Open twelve 300-mg ursodiol capsules and wet with sufficient glycerin, USP. Triturate to make a fine paste. Gradually add Simple Syrup, USP to make a final volume of 60 ml. Label 'shake well'. The suspension was stable for 35 days when stored in the dark in glass amber-colored bottles at 4 degrees C.

Ursodeoxycholic acid, ursodiol is typically well-tolerated, in both the pediatric and adult populations. Side effects reported in >= 5% of patients taking ursodiol often occur at rates similar to placebo in controlled trials.

GI-related side effects have been reported with ursodiol, but the actual incidences are difficult to determine because the effects may reflect the underlying disease for which the patient is treated. Such effects include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea, and vomiting. Increased bilirubin (hyperbilirubinemia), elevated hepatic enzymes, and jaundice (or aggravation or preexisting jaundice) have been reported in postmarketing experience. Liver function tests (LFTs) and bilirubin levels should be monitored every month for 3 months after initiation of therapy and every 6 months thereafter. Consider treatment discontinuation if LFTs increase to a level of clinical concern in patients with stable LFTs at baseline. Caution should be exercised to maintain the bile flow of patients taking ursodiol.

Side effects reported in clinical trials at a slightly higher incidence with ursodeoxycholic acid, ursodiol than with placebo included arthralgia, (arthritis-type symptoms) and myalgia. The following events occurred more often in ursodiol groups than placebo in trials for biliary cirrhosis (PBC), but no assessment of causality is available: elevated serum creatinine, hyperglycemia, leukopenia, peptic ulcer, and skin rash (unspecified). Clinical studies report a similar incidence of CNS side effects for both ursodiol and placebo, including headache and dizziness. Malaise and pyrexia (fever) have been reported with postmarketing experience.

Respiratory side effects have been reported with ursodeoxycholic acid, ursodiol. They include bronchitis, cough, pharyngitis, rhinitis, sinusitis and upper respiratory tract infection. Of the side effects reported, only bronchitis, cough, and pharyngitis occurred more often with ursodiol than with placebo.

Very rarely, allergic reactions to bile acid agents may occur. Anaphylactoid reactions, skin rash (unspecified), urticaria, or other allergic-type symptoms have been reported. Alopecia has been reported with ursodeoxycholic acid, ursodiol use. Reported postmarketing drug hypersensitively reactions include facial edema, angioedema, and laryngeal edema.

In a phase IV post-marketing study, 60 adult patients with primary biliary cirrhosis were given ursodiol in varying regimens of a single or a daily divided dose. Four of the sixty patients (6.7%) experienced one serious event each, new onset diabetes mellitus, cyst, and two patients experienced a breast neoplasm. The causality of these findings is difficult to asses; however 43 (71.7%) patients did report side effects that were considered treatment emergent adverse events. These included asthenia (11.7%), dyspepsia (10%), peripheral edema (8.3%), hypertension (8.3%), nausea (8.3%), GI disorders (5%), chest pain (unspecified) (5%), and pruritus (5%). Other reported side effects judged to be possibly drug related were anorexia and esophagitis reported by one patient each. Discontinuation of treatment occurred in one patient due to intractable nausea. All treatment emergent adverse events were observed in patients receiving a twice daily dose of ursodiol at a total dose of 1000 mg or greater.

In placebo controlled trials with ursodiol, thrombocytopenia was reported in 1 adult patient (1.32%) at the 24 month visit.

In adult clinical studies, dysmenorrhea, musculoskeletal pain, influenza-like symptoms, and viral infections were reported with ursodiol; the incidence was similar between ursodiol and placebo.

Ursodeoxycholic acid, ursodiol will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Therefore, patients with these types of stones are not candidates for ursodeoxycholic acid, ursodiol therapy.

Ursodeoxycholic acid, ursodiol is contraindicated for use in patients hypersensitive to ursodiol, the formulation, or with other bile acid agents hypersensitivity.

Ursodiol is contraindicated in patients with complete biliary obstruction. Patients with cholelithiasis or biliary tract disease and compelling reasons for cholecystectomy, including unremitting acute cholecystitis, cholangitis, gallstone pancreatitis, or biliary-GI fistula are not candidates for gallstone dissolution via use of ursodeoxycholic acid, ursodiol. Use with caution in patients with hepatobiliary disorders; jaundice, aggravation of pre-existing jaundice, and elevated hepatic enzymes have been reported in postmarketing safety surveillance. Measure LFTs and bilirubin at baseline, monthly for 3 months after start of therapy, and then every 6 months thereafter. If clinically significant increases in LFTs or bilirubin concentrations occur in patients with previously stable hepatic function, consider discontinuing ursodiol therapy. Patients with primary biliary cirrhosis or other cholestatic hepatic disease complicated with concomitant ascites, hepatic encephalopathy, variceal bleeding (e.g. bleeding esophageal varices), or with the need for an urgent organ transplant of the liver should receive appropriate specific treatment.

Description: Ursodeoxycholic acid, ursodiol is an oral, naturally occurring bile acid agent. Ursodiol is FDA-approved to solubilize radiolucent (cholesterol) gallstones, prevent gallstone formation in obese patients experiencing rapid weight loss, and for the treatment of patients with primary biliary cirrhosis. Gallstone dissolution requires months of therapy, and complete dissolution may not occur in all patients. The drug helps prevent gallstones during rapid weight loss. Ursodiol is used off-label as an adjunct in treating cholestatic hepatobiliary diseases in adults and pediatric patients. In pediatric patients it is used most often for treatment of cholestasis associated with parenteral nutrition, biliary atresia, and liver disease in patients with cystic fibrosis. In these hepatobiliary disorders, ursodiol reduces cholestasis, pruritus, and elevated hepatic enzymes, but slowing of disease progression to cirrhosis is not always evident. In clinical trials, ursodiol was not associated with hepatotoxicity; however, elevated hepatic enzymes and jaundice have been reported during postmarketing safety surveillance. Monitoring of liver enzymes and bilirubin is recommended during therapy. Although not FDA- approved, ursodiol has been used off-label in pediatric patients as young as neonates.

For the treatment of cholestasis* (e.g., cholestasis due to parenteral nutrition, biliary atresia, intestinal failure, cystic fibrosis):
Oral dosage:
Premature Neonates and Neonates: 10-30 mg/kg/day in 3 divided doses has been used in neonates with cholestasis due to primary intestinal failure and TPN-associated cholestasis. Doses of 20 to 40 mg/kg/day have been used for the treatment of neonatal hepatitis and in neonates with cystic fibrosis.
Infants, Children, and Adolescents: 15-30 mg/kg/day is used in patients with TPN-associated cholestasis. Doses of 10-30 mg/kg/day are commonly used for cholestasis secondary to bliliary atresia or cystic fibrosis; however, doses up to 40 mg/kg/day have been reported in infants with cystic fibrosis.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however off-label doses of up to 30 mg/kg/day have been used. For cystic fibrosis and neonatal hepatitis, doses up to 40 mg/kg/day PO have been used in term neonates.
-Infants
Safety and efficacy have not been established; however off-label doses of up to 30 mg/kg/day for most uses and 40 mg/kg/day PO for cystic fibrosis have been used.
-Children
Safety and efficacy have not been established; however doses up to 30 mg/kg/day PO have been used off-label.
-Adolescents
Safety and efficacy have not been established; however doses up to 30 mg/kg/day PO have been used off-label.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustment in hepatic impairment are not available; it appears that no dosage adjustments are needed. The amount of accumulation that might occur in severe hepatic disease does not appear to be clinically significant.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustment in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action:-Primary biliary cirrhosis (PBC) and other cholestatic liver diseases: Retardation of disease progression has been noted in clinical trials for PBC. Ursodiol's benefit in other hepatic diseases has been to reduce LFTs and clinical symptoms (e.g., pruritus). The exact mechanism by which ursodiol slows the progression of liver disease in patients with primary biliary cirrhosis is unclear. Retention of high concentrations of hydrophobic bile acids within hepatocytes during cholestasis has been shown to damage the membranes of intracellular organelles. Improved hepatic bile flow, decreased bile viscosity, reduced ductular proliferation, and reduced portal inflammation appear to be important effects of ursodiol. Ursodiol has been shown to reduce the intrahepatic concentration of hydrophobic bile acids within hepatocytes, and to increase the hydrophilicity of the bile acid pool. Ursodiol also interferes with the enterohepatic circulation of bile acids by inhibiting reuptake of endogenous bile acids in the terminal ileum. Studies have suggested that ursodiol may have an immunomodulatory effect and inhibit the production of certain cytotoxic cytokines, which may reduce lipid peroxidation in hepatocytes.
-Cystic fibrosis liver disease: In clinical trials, ursodiol administration has improved liver function tests and increased biliary excretion in patients with cystic fibrosis. Cystic fibrosis patients are thought to benefit from ursodiol administration by several different mechanisms. The exact mechanism by which ursodiol improves liver function tests and increases biliary excretion is unknown, but it is thought to be due to its "choleretic" effect, which increases bile acid-dependent bile flow improving the fluidity of the bile; the "hepatoprotective" effect where it replaces the more hydrophobic and potentially toxic bile acids; the immunomodulatory effect that inhibits the production of certain cytotic cytokines; and improvement of biliary drainage.
-Gallstone dissolution: Ursodiol decreases the cholesterol content of bile and associated gallstones by reducing the hepatic synthesis and secretion of cholesterol and the fractional reabsorption of cholesterol by the intestine. Ursodiol does not inhibit the synthesis and secretion of endogenous bile acids or phospholipids into the bile. In addition to solubilizing cholesterol in micelles, ursodiol causes dispersion of cholesterol as liquid crystals in aqueous media. The actions of ursodiol change the nature of the bile from cholesterol-precipitating to cholesterol-solubilizing, thus resulting in an environment conducive to gallstone dissolution.

Pharmacokinetics: Ursodiol is administered orally. Approximately 90% of ursodiol is absorbed in the small bowel after oral administration. Only small amounts of ursodiol appear in the systemic circulation and very small amounts are excreted into the urine. With repeated dosing, bile ursodiol concentrations reach a steady-state in about 3 weeks; ursodiol concentrations in the bile do not exceed 60% of the total bile acid pool. After ursodiol is discontinued, the concentration of the drug in bile falls exponentially, declining to roughly 5-10% of its steady-state level within 1 week.

Beyond conjugation, ursodiol is not catabolized appreciably by the liver or intestinal mucosa. A small proportion of the orally administered drug undergoes bacterial degradation in the intestine with each cycle of enterohepatic circulation. Ursodiol can be both oxidized and reduced, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, the conjugated glyco- or tauro-ursodiol may be deconjugated in the small bowel, yielding free ursodiol. All of these bacterial degradation products are relatively insoluble and large proportions of these products are excreted in the feces. Some free ursodiol is reabsorbed and reconjugated by the liver. Eighty-percent of the lithocholic acid formed in the small bowel is excreted in the feces, but 20% is reabsorbed and then sulfated by the liver to lithocholyl conjugates excreted in the bile and lost in the feces. Small amounts of 7-keto-lithocholic acid are reabsorbed and stereospecifically reduced by the liver to chenodiol.

Affected cytochrome P450 isoenzymes: none