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Ursodiol


General


Pronunciation

(ur soe DYE ol)


Brand Names: U.S.

  • Actigall
  • Urso 250
  • Urso Forte

Indications


Use: Labeled Indications

Gallstones (capsules only):

For patients with radiolucent, noncalcified gallbladder stones less than 20 mm in greatest diameter in whom elective cholecystectomy would be undertaken except for the presence of increased surgical risk caused by systemic disease, advanced age, idiosyncratic reaction to general anesthesia, or for those patients who refuse surgery. Safety for use of ursodiol beyond 24 months is not established.

For the prevention of gallstone formation in obese patients experiencing rapid weight loss.

Primary biliary cirrhosis (tablets only): For the treatment of patients with primary biliary cirrhosis (PBC).


Contraindications


Hypersensitivity to ursodiol or any component of the formulation; not to be used with calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones; patients with unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-gastrointestinal fistula; allergy to bile acids


Dosing and Administration


Dosing: Adult

Gallstone dissolution (Actigall): Oral: 8-10 mg/kg/day in 2-3 divided doses; use beyond 24 months is not established

Gallstone prevention (Actigall): Oral: 300 mg twice daily

Primary biliary cirrhosis (Urso, Urso Forte): Oral: 13-15 mg/kg/day in 2-4 divided doses (with food)


Dosing: Geriatric

Refer to adult dosing.


Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer 's labeling.


Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer 's labeling.


Administration

Do not administer with aluminum-based antacids or bile acid sequestrants. If aluminum-based antacids are needed, administer 2 hours after ursodiol; administer ursodiol 5 hours or more after bile acid sequestrants (Rust, 2000). Urso Forte can be split into halves for appropriate dosage; do not chew. Urso and Urso Forte should be taken with food.


Dietary Considerations

Urso and Urso Forte should be taken with food.


Storage

Actigall: Store at 25 ‚ °C (77 ‚ °F); excursions permitted to 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F).

Urso: Store at 20 ‚ °C to 25 ‚ °C (68 ‚ °F to 77 ‚ °F).

Urso Forte: Store at 20 ‚ °C to 25 ‚ °C (68 ‚ °F to 77 ‚ °F). When broken in half, scored Urso Forte 500 mg tablets maintain quality for up to 28 days when kept in current packaging and stored at 20 ‚ °C to 25 ‚ °C (68 ‚ °F to 77 ‚ °F). Split tablets should be stored separately from whole tablets due to bitter taste.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Actigall: 300 mg

Generic: 300 mg

Tablet, Oral:

Urso 250: 250 mg

Urso Forte: 500 mg [scored]

Generic: 250 mg, 500 mg


Extemporaneously Prepared

A 20 mg/mL ursodiol oral suspension may be made with capsules and either a 1:1 mixture of Ora-Sweet and Ora-Plus or a 1:1 mixture of methylcellulose 1% and syrup NF. Empty the contents of seventeen 300 mg capsules into a mortar. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 255 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 255 mL. Label shake well" and "refrigerate". Stable for 91 days refrigerated (Nahata, 1999).

A 25 mg/mL ursodiol oral suspension may be made with capsules. Empty the contents of ten 300 mg capsules into a mortar; add 10 mL Glycerin, USP and mix until smooth. Mix while adding 60 mL Ora-Plus; transfer mixture to a light-resistant bottle, rinse mortar with a small amount of Orange Syrup, NF, and add quantity of syrup sufficient to make 120 mL. Label shake well". Stable for 60 days at room temperature or refrigerated (Mallett, 1997).

A 50 mg/mL ursodiol oral suspension may be made with tablets and 60 mL of either a 1:1 mixture of Ora-Plus and strawberry syrup or a 1:1 mixture of Ora-Plus and Ora-Sweet SF. Crush twelve 250 mg tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label shake well" and "refrigerate". Stable for 90 days refrigerated (Johnson, 2002).

A 60 mg/mL ursodiol oral suspension may be made with capsules. Empty the contents of twelve 300 mg capsules into a mortar. Add small portions of glycerin and mix to a uniform paste; mix while adding simple syrup in incremental proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label shake well" and "refrigerate". Stable for 35 days refrigerated (Johnson, 1995).

Johnson CE and Nesbitt J, "Stability of Ursodiol in an Extemporaneously Compounded Oral Liquid," Am J Health Syst Pharm, 1995, 52(16):1798-1800.[PMID: 8528836]Johnson CE and Streetman DD, "Stability of Oral Suspensions of Ursodiol Made From Tablets," Am J Health Syst Pharm, 2002, 59(4):361-3.[PMID: 11885400]Mallett MS, Hagan RL, and Peters DA, "Stability of Ursodiol 25 mg/mL in an Extemporaneously Prepared Oral Liquid," Am J Health Syst Pharm, 1997, 54(12):1401-4.[PMID: 9194984]Nahata MC, Morosco RS, and Hipple TF, "Stability of Ursodiol in Two Extemporaneously Prepared Oral Suspensions," J Appl Ther Res, 1999, 2:221-4.

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Ursodiol. Management: Consider administration of ursodiol 2 hours before or 6 hours after aluminum-containing antacid products to prevent adsorption in the gastrointestinal tract. Consider therapy modification

Bile Acid Sequestrants: May decrease the serum concentration of Ursodiol. Management: Administer ursodiol 5 hours or more after bile acid sequestrants to minimize ursodiol adsorption in the gastrointestinal tract. Monitor for decreased therapeutic effects of ursodiol in patients receiving bile acid sequestrants. Consider therapy modification

Estrogen Derivatives: May diminish the therapeutic effect of Ursodiol. Monitor therapy

Fibric Acid Derivatives: May diminish the therapeutic effect of Ursodiol. Monitor therapy

Nitrendipine: Ursodiol may decrease the absorption of Nitrendipine. Management: Consider therapeutic alternatives. If concomitant therapy cannot be avoided, avoid simultaneous administration. Consider therapy modification


Monitoring Parameters

Gallstone disease: ALT, AST, sonogram

Hepatic disease: Monitor liver function tests (GGT, AST, ALT, bilirubin, and alkaline phosphatase) monthly for the first 3 months and every 6 months thereafter or as clinically necessary.


Adverse Reactions


>10%:

Central nervous system: Headache ( ≤25%), dizziness (17%)

Gastrointestinal: Diarrhea ( ≤27%), constipation ( ≤26%), dyspepsia ( ≤17%), nausea ( ≤17%)

Neuromuscular & skeletal: Back pain ( ≤12%)

Respiratory: Upper respiratory tract infection ( ≤16%)

1% to 10%:

Dermatologic: Alopecia (5%), skin rash (3%)

Endocrine & metabolic: Hyperglycemia (1%)

Gastrointestinal: Vomiting ( ≤10%), peptic ulcer (1%)

Genitourinary: Urinary tract infection (7%)

Hematologic & oncologic: Leukopenia (3%), thrombocytopenia (1%)

Hepatic: Cholecystitis (5%)

Hypersensitivity: Hypersensitivity reaction (5%)

Infection: Viral infection (9%)

Neuromuscular & skeletal: Arthritis (6%), musculoskeletal pain (6%)

Renal: Increased serum creatinine (1%)

Respiratory: Pharyngitis ( ≤8%), bronchitis (7%), cough (7%), flu-like symptoms (7%)

<1% (Limited to important or life-threatening): Abdominal distress, abdominal pain, abnormal hepatic function tests, angioedema, anorexia, biliary colic, esophagitis, facial edema, fever, hepatobiliary disease, increased gamma-glutamyl transferase, increased liver enzymes, increased serum alkaline phosphatase, increased serum ALT, increased serum AST, increased serum bilirubin, jaundice, laryngeal edema, malaise, metallic taste, myalgia, peripheral edema, pruritus, transaminases increased, urticaria, weakness


Warnings/Precautions


Concerns related to adverse effects:

- Biliary obstruction: Maintain bile flow during therapy to prevent biliary obstruction.

Disease-related concerns:

- Hepatic effects: Use with caution in patients with chronic liver disease; monitor liver function tests monthly for the first 3 months, and every 6 months thereafter or as clinically necessary. Discontinuation of therapy may be necessary with significant elevations in liver function tests.

Other warnings/precautions:

- Appropriate use: Gallbladder stone dissolution may take several months of therapy; complete dissolution may not occur and recurrence of stones within 5 years has been observed in up to 50% of patients. Patients should be cautiously selected for therapy, consider alternative treatments. Specific treatments should be initiated in patients with ascites, hepatic encephalopathy, variceal bleeding, or if an urgent liver transplant is necessary.

- Nonvisualizing gallbladder: Use with caution in patients with a nonvisualizing gallbladder; therapy should be discontinued if gallbladder nonvisualization occurs during treatment.


Pregnancy Risk Factor

B


Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Ursodiol (ursodeoxycholic acid) is the treatment of choice for intrahepatic cholestasis of pregnancy (Kremer, 2011).


Actions


Pharmacology

Decreases the cholesterol content of bile and bile stones by reducing the secretion of cholesterol from the liver and the fractional reabsorption of cholesterol by the intestines. Mechanism of action in primary biliary cirrhosis is not clearly defined.


Absorption

90%


Metabolism

Undergoes extensive enterohepatic recycling; following hepatic conjugation and biliary secretion, the drug is hydrolyzed to active ursodiol, where it is recycled or transformed to lithocholic acid by colonic microbial flora; during chronic administration, ursodiol becomes a major biliary and plasma bile acid constituting 30% to 50% of biliary and plasma bile acids


Excretion

Feces; urine (<1%)


Protein Binding

~70%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience dizziness, headache, back pain, nausea, vomiting, constipation, diarrhea, abdominal pain, or heartburn (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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