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  • CLASSES

    Bile Acid Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, naturally occurring, well-tolerated bile acid agent.
    Will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones.
    Monitoring of liver enzymes and bilirubin is recommended during therapy.

    COMMON BRAND NAMES

    Actigall, Urso 250, Urso Forte

    HOW SUPPLIED

    Actigall/Ursodiol Oral Cap: 300mg
    Urso 250/Urso Forte/Ursodiol Oral Tab: 250mg, 500mg

    DOSAGE & INDICATIONS

    For treatment of cholelithiasis via the dissolution of radiolucent cholesterol gallstones.
    For gallstone dissolution via use of ursodiol alone.
    Oral dosage (Actigall)
    Adults

    8—10 mg/kg/day PO, given in 2—3 divided doses. Dissolution of gallstones may require many months of treatment. Ultrasound imaging of the gallbladder should be performed at 6-month intervals for the first year. After complete dissolution is documented, continue ursodiol for 3 months to dissolve remaining stone particles that may be undetected by ultrasound. Dissolution is most likely to occur in patients who are non-obese with non-calcified stones < 20 mm in diameter. Up to 50% of patients will experience gallstone recurrence within 5 years.

    For treating single radiolucent gallstones of 4—20 mm diameter by combining ursodiol therapy with lithotripsy (e.g., Medstone).
    Oral dosage (Actigall)
    Adults (non-pregnant)

    Initiate treatment 2 weeks prior to lithotripsy at a dose of 8—10 mg/kg/day PO, given in 2—3 divided doses. After lithotripsy, continue ursodiol until dissolution is apparent (usually 6—24 months). The success-rate of the combined treatments is roughly 45%.

    For gallstone prophylaxis during rapid weight loss.
    Oral dosage (Actigall)
    Adults

    300 mg PO twice daily.

    For the treatment of cholestatic hepatobiliary disorders and their symptoms (e.g., pruritus†).
    For the treatment of primary biliary cirrhosis (PBC).
    NOTE: Ursodiol is designated an orphan drug by the FDA for this indication.
    Oral dosage (Urso tablets)
    Adults

    13—15 mg/kg/day PO administered in two to four divided doses. Ursodiol slows disease progression and reduces the need for liver transplantation. Predictive factors for ursodiol failures include high serum bilirubin, high total serum bile acid concentrations, low serum albumin, hepatomegaly, or splenomegaly.

    For the treatment of cholestasis† secondary to cystic fibrosis†.
    Oral dosage
     Infants and Children

    Data are limited. Initially, 30—45 mg/kg/day PO may be required; doses of at least 20 mg/kg/day PO are usually needed.

    For the treatment of intrahepatic cholestasis of pregnancy (ICP)†.
    Oral dosage
    Adult pregnant females

    Dosages range from 5—20 mg/kg/day PO. Also, 500 mg PO twice daily has been used in a controlled trial (roughly 16 mg/kg/day PO).

    For the treatment of primary sclerosing cholangitis (PSC)†.
    Oral dosage
    Adults

    13—15 mg/kg/day PO, administered in divided doses, may improve LFTs and reduce fatigue and pruritus; however, histologic or survival benefits for PSC are uncertain. Retrospective data suggest that patients with UC and concomitant PSC who are exposed to ursodiol are less likely to develop colonic dysplasia than non-users. The hypothesis is still untested and unproved. Ursodiol should only be used for this indication within the context of a clinical trial.

    Children

    Data are limited; pediatric GI specialists often use 13—25 mg/kg/day PO to control symptoms. Whether ursodiol reduces or prevents the progression of PSC is unknown.

    For use as an adjunct to prevent biliary stent occlusion† after surgical placement to palliate malignant biliary obstruction secondary to pancreatic cancer.
    Oral dosage
    Adults

    Data are limited; ursodiol 13—15 mg/kg/day PO in combination with norfloxacin 400 mg/day PO may help maintain biliary stent patency.

    For adjunctive treatment of biliary atresia or chronic cholestasis (e.g., genetic bile acid biosynthesis disorder).
    Oral dosage
    Infants and Children

    10—20 mg/kg PO once daily at bedtime has been suggested. Up to 40 mg/kg/day PO has been used after surgery for biliary atresia to prevent cholangitis.

    For the treatment of non-alcoholic steatosis-hepatitis (NASH)†.
    Oral dosage
    Adults

    Preliminary data suggest 13—15 mg/kg/day PO, given in divided doses, is clinically beneficial (i.e., improves LFTs and histologic status of NASH). Results need confirmation in controlled trials.

    Children >= 4 years

    One trial used 10—12.5 mg/kg/day PO given in two divided doses. However, ursodiol plus a weight-reducing diet and exercise was no more efficacious than weight loss alone.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage information is not available.

    Elderly

    Maximum dosage information is not available.

    Adolescents

    Maximum dosage information is not available.

    Children

    Maximum dosage information is not available.

    Infants

    Maximum dosage information is not available.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Follow normal dosage. The amount of accumulation that might occur in severe hepatic disease does not appear to be clinically significant.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer ursodiol orally with food or milk; infants may receive ursodiol with milk, formula, or soft food.

    Extemporaneous Compounding-Oral

    Shake well before use. Administer using a calibrated oral syringe or dosage cup.
     
    Extemporaneous preparation of oral suspensions† (not commercially available in the US):
    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 is stable for 35 days in the refrigerator (at 4 degrees C).

    STORAGE

    Actigall:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Urso 250:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Urso Forte:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.
     
    The safety and effectiveness of ursodiol for cholelithiasis in children have not been established. However, trials of ursodiol for the treatment of cholestatic liver diseases in children, infants, and neonates have not indicated problems that would limit the drug's usefulness for studied off-label indications.

    Bile acid agents hypersensitivity

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

    Ascites, biliary obstruction, biliary tract disease, biliary-GI fistula, bleeding, cholangitis, encephalopathy, esophageal varices, jaundice, pancreatitis

    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.

    Pregnancy

    Ursodiol is classified in FDA pregnancy risk category B. Animal studies 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; use during pregnancy only if clearly needed. Ursodiol has been used effectively and safely in women with intrahepatic cholestasis of pregnancy (ICP) in several clinical trials; current evidence is insufficient to definitively determine maternal or fetal safety; however, Gastroenterology experts consider the drug low risk based on available data. There are no published experiences with ursodiol for gallstone dissolution during pregnancy. Clinicians should note that the use of extracorporeal shock wave lithotripsy (ESWL), a procedure where ursodiol may be used adjunctively, is contraindicated in pregnant women.

    Breast-feeding

    According to the manufacturer, caution should be exercised when ursodiol is administered during breast-feeding; however, problems in humans have not been documented. It is not known if ursodiol is excreted in human milk. However, because only small amounts of ursodiol reach the systemic maternal circulation, it is unlikely that clinically significant amounts would reach the breast-fed infant. Gastroenterology experts consider the drug to be "probably" compatible with lactation.

    Geriatric

    Roughly 14% of the subjects in ursodiol clinical trials were over 65 years of age (with 3% of these over the age of 75). In a subgroup analysis, no efficacy difference has been found in rates of dissolution of gallstones of patients older than 56 years of age vs. younger patients. However, it is recommended to dose ursodiol cautiously in geriatric patients, as small differences in efficacy and/or safety cannot be completely ruled out.

    ADVERSE REACTIONS

    Severe

    peptic ulcer / Delayed / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    thrombocytopenia / Delayed / 1.3-1.3
    esophagitis / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypertension / Early / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    dyspepsia / Early / 10.0-10.0
    nausea / Early / 8.3-8.3
    pruritus / Rapid / 5.0-5.0
    vomiting / Early / 0-1.0
    flatulence / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    fever / Early / Incidence not known
    myalgia / Early / Incidence not known
    headache / Early / Incidence not known
    dizziness / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    malaise / Early / Incidence not known
    rhinitis / Early / Incidence not known
    cough / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    dysmenorrhea / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    Aluminum Hydroxide: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
    Charcoal: (Major) Activated charcoal, which is available in dietary supplements, has been shown to adsorb bile acids in vitro and is expected to interfere with the efficacy of ursodeoxycholic acid, ursodiol. Concurrent use is not recommended.
    Cholestyramine: (Moderate) Cholestyramine may interfere with the action of ursodeoxycholic acid, ursodiol by reducing its absorption. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 4 to 6 hours after the bile acid sequestering agents.
    Ciprofloxacin: (Moderate) There has been one case report of reduced serum concentrations of ciprofloxacin after the administration of ursodeoxycholic acid, ursodiol to a patient with hepatobiliary disease. The mechanism of the proposed interaction is uncertain.
    Colesevelam: (Moderate) Colesevelam may interfere with the action of ursodeoxycholic acid, ursodiol by reducing its absorption. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 4 hours after the bile acid sequestering agents.
    Colestipol: (Moderate) Colestipol may interfere with the action of ursodeoxycholic acid, ursodiol by reducing its absorption. To minimize drug interactions, administer ursodiol at least 1 hour before or at least 4 hours after the bile acid sequestering agents.
    Estrogens: (Minor) Estrogens and combined hormonal and oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation, and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
    Fenofibrate: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
    Fenofibric Acid: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
    Fibric acid derivatives: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
    Gemfibrozil: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.

    PREGNANCY AND LACTATION

    Pregnancy

    Ursodiol is classified in FDA pregnancy risk category B. Animal studies 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; use during pregnancy only if clearly needed. Ursodiol has been used effectively and safely in women with intrahepatic cholestasis of pregnancy (ICP) in several clinical trials; current evidence is insufficient to definitively determine maternal or fetal safety; however, Gastroenterology experts consider the drug low risk based on available data. There are no published experiences with ursodiol for gallstone dissolution during pregnancy. Clinicians should note that the use of extracorporeal shock wave lithotripsy (ESWL), a procedure where ursodiol may be used adjunctively, is contraindicated in pregnant women.

    According to the manufacturer, caution should be exercised when ursodiol is administered during breast-feeding; however, problems in humans have not been documented. It is not known if ursodiol is excreted in human milk. However, because only small amounts of ursodiol reach the systemic maternal circulation, it is unlikely that clinically significant amounts would reach the breast-fed infant. Gastroenterology experts consider the drug to be "probably" compatible with lactation.

    MECHANISM OF ACTION

    Mechanism of Action: Ursodiol's therapeutic sites of action are in the liver, bile, and gut lumen. At chronic doses of 13—15 mg/kg/day, ursodiol constitutes roughly 30—50% of the total biliary and plasma bile acids.•Mechanism of 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.•Mechanism in primary biliary cirrhosis (PBC) and other cholestatic liver diseases: Retardation of disease progression has only been noted in clinical trials for PBC; further investigation is needed to prove ursodiol retards the progression to cirrhosis in other cholestatic liver diseases. Ursodiol's benefit to date in other hepatic diseases has been a reduction in LFTs and clinical symptoms (e.g., pruritus). The exact mechanism by which ursodiol retards progression of liver disease in patients with primary biliary cirrhosis is still 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.

    PHARMACOKINETICS

    Ursodiol is administered orally. 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. rsodiol 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.

    Oral Route

    Following oral administration, ursodiol is absorbed via passive diffusion. Roughly 90% of a therapeutic dose is absorbed in the small intestine, after which it enters the portal vein and is extracted from the portal blood by the liver. In the liver, ursodiol is conjugated with either glycine or taurine, then is secreted into the hepatic bile ducts. Ursodiol is then concentrated into the bile in the gallbladder. Ursodiol and the other bile acids are expelled into the duodenum via the cystic and common bile ducts by gallbladder contractions induced by the physiologic response to oral ingestion of food.