Actigall

Bile Acid Agents

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

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).

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

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

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 / 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

Actigall, Reltone, Urso 250, Urso Forte

Rx

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.

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

No dosage adjustments are needed.

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.

Actigall/Reltone/Ursodiol Oral Cap: 200mg, 300mg, 400mg
Urso 250/Urso Forte/Ursodiol Oral Tab: 250mg, 500mg

Maximum dosage information is not available.

Maximum dosage information is not available.

Safety and efficacy have not been established; however doses up to 30 mg/kg/day PO have been used off-label.

Safety and efficacy have not been established; however doses up to 30 mg/kg/day PO have been used off-label.

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.

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.

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.

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.

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.

Available published data on the use of ursodiol during pregnancy, derived from randomized controlled trials, observational studies, and case series collected over several decades, have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Most of the reported exposures to ursodiol occurred in the second and third trimester of pregnancy. In animal reproduction studies, ursodiol had no adverse effects on embryo-fetal development when administered at doses greater than human therapeutic doses. 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.[26354] [45899]

Ursodiol is naturally present in human milk. There are no reports of adverse effects of ursodiol on the breastfed child, but the reports are extremely limited. There are no data on the effects of ursodiol on milk production. 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 breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.