Prescription Drug Information: Ursodiol (Page 2 of 3)

INDICATIONS AND USAGE

  • Ursodiol capsules, USP are indicated for patients with radiolucent, noncalcified gallbladder stones < 20 mm in greatest diameter in whom elective cholecystectomy would be undertaken except for the presence of increased surgical risk due to systemic disease, advanced age, idiosyncratic reaction to general anesthesia, or for those patients who refuse surgery. Safety of use of ursodiol capsules beyond 24 months is not established.
  • Ursodiol capsules are indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.

CONTRAINDICATIONS

  • Ursodiol capsules will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Hence, patients with such stones are not candidates for ursodiol therapy.
  • Patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-gastrointestinal fistula are not candidates for ursodiol therapy.
  • Allergy to bile acids.

PRECAUTIONS

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. This bile acid is formed in the gut from ursodiol less efficiently and in smaller amounts than that seen from chenodiol. 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 lithocholate-induced liver damage.

Abnormalities in liver enzymes have not been associated with ursodiol therapy and, in fact, ursodiol has been shown to decrease liver enzyme levels in liver disease. However, patients given ursodiol should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances.

Drug Interactions

Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids in vitro and may be expected to interfere with ursodiol in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodiol.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ursodeoxycholic acid was tested in 2-year oral carcinogenicity studies in CD-1 mice and Sprague-Dawley rats at daily doses of 50, 250, and 1000 mg/kg/day. It was not tumorigenic in mice. In the rat study, it produced statistically significant dose related increased incidences of pheochromocytomas of adrenal medulla in males (p = 0.014, Peto trend test) and females (p = 0.004, Peto trend test.) A 78-week rat study employing intrarectal instillation of lithocholic acid and tauro-deoxycholic acid, metabolites of ursodiol and chenodiol, has been conducted. These bile acids alone did not produce any tumors. A tumor-promoting effect of both metabolites was observed when they were coadministered with a carcinogenic agent. Results of epidemiologic studies suggest that bile acids might be involved in the pathogenesis of human colon cancer in patients who had undergone a cholecystectomy, but direct evidence is lacking. Ursodiol is not mutagenic in the Ames test. Dietary administration of lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.

Pregnancy

Teratogenic Effects. Pregnancy Category B

Reproduction studies have been performed in rats and rabbits with ursodiol doses up to 200-fold the therapeutic dose and have revealed no evidence of impaired fertility or harm to the fetus at doses of 20- to 100-fold the human dose in rats and at 5-fold the human dose (highest dose tested) in rabbits. Studies employing 100- to 200-fold the human dose in rats have shown some reduction in fertility rate and litter size. There have been no adequate and well controlled studies of the use of ursodiol in pregnant women, but inadvertent exposure of four women to therapeutic doses of the drug in the first trimester of pregnancy during the ursodiol trials led to no evidence of effects on the fetus or newborn baby. Although it seems unlikely, the possibility that ursodiol can cause fetal harm cannot be ruled out; hence, the drug is not recommended for use during pregnancy.

Nursing Mothers

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.

Pediatric Use

The safety and effectiveness of ursodiol in pediatric patients have not been established.

Geriatric Use

In worldwide clinical studies of ursodiol, approximately 14% of subjects were over 65 years of age (approximately 3% were over 75 years old). In a subgroup analysis of existing clinical trials, patients greater than 56 years of age did not exhibit statistically significantly different complete dissolution rates from the younger population. No age-related differences in safety and effectiveness were found. Other reported clinical experience has not identified differences in response in elderly and younger patients. However, small differences in efficacy and greater sensitivity of some elderly individuals taking ursodiol cannot be ruled out. Therefore, it is recommended that dosing proceed with caution in this population.

ADVERSE REACTIONS

The nature and frequency of adverse experiences were similar across all groups.

The following tables provide comprehensive listings of the adverse experiences reported that occurred with a 5% incidence level:

GALLSTONE DISSOLUTION

Ursodiol
8 to 10 mg/kg/day

Placebo

(N = 155)

(N = 159)

N

(%)

N

(%)

Body as a Whole

Allergy

8

(5.2)

7

(4.4)

Chest Pain

5

(3.2)

10

(6.3)

Fatigue

7

(4.5)

8

(5)

Infection Viral

30

(19.4)

41

(25.8)

Digestive System

Abdominal Pain

67

(43.2)

70

(44)

Cholecystitis

8

(5.2)

7

(4.4)

Constipation

15

(9.7)

14

(8.8)

Diarrhea

42

(27.1)

34

(21.4)

Dyspepsia

26

(16.8)

18

(11.3)

Flatulence

12

(7.7)

12

(7.5)

Gastrointestinal Disorder

6

(3.9)

8

(5)

Nausea

22

(14.2)

27

(17)

Vomiting

15

(9.7)

11

(6.9)

Musculoskeletal System

Arthralgia

12

(7.7)

24

(15.1)

Arthritis

9

(5.8)

4

(2.5)

Back Pain

11

(7.1)

18

(11.3)

Myalgia

9

(5.8)

9

(5.7)

Nervous System

Headache

28

(18.1)

34

(21.4)

Insomnia

3

(1.9)

8

(5)

Respiratory System

Bronchitis

10

(6.5)

6

(3.8)

Coughing

11

(7.1)

7

(4.4)

Pharyngitis

13

(8.4)

5

(3.1)

Rhinitis

8

(5.2)

11

(6.9)

Sinusitis

17

(11)

18

(11.3)

Upper Respiratory Tract Infection

24

(15.5)

21

(13.2)

Urogenital System

Urinary Tract Infection

10

(6.5)

7

(4.4)

GALLSTONE PREVENTION

Ursodiol

Placebo

600 mg

(N = 322)

(N = 325)

N

(%)

N

(%)

Body as a Whole

Fatigue

25

(7.8)

33

(10.2)

Infection Viral

29

(9)

29

(8.9)

Influenza-like Symptoms

21

(6.5)

19

(5.8)

Digestive System

Abdominal Pain

20

(6.2)

39

(12)

Constipation

85

(26.4)

72

(22.2)

Diarrhea

81

(25.2)

68

(20.9)

Flatulence

15

(4.7)

24

(7.4)

Nausea

56

(17.4)

43

(13.2)

Vomiting

44

(13.7)

44

(13.5)

Musculoskeletal System

Back Pain

38

(11.8)

21

(6.5)

Musculoskeletal Pain

19

(5.9)

15

(4.6)

Nervous System

Dizziness

53

(16.5)

42

(12.9)

Headache

80

(24.8)

78

(24)

Respiratory System

Pharyngitis

10

(3.1)

19

(5.8)

Sinusitis

17

(5.3)

18

(5.5)

Upper Respiratory Tract Infection

40

(12.4)

35

(10.8)

Skin and Appendages

Alopecia

17

(5.3)

8

(2.5)

Urogenital System

Dysmenorrhea

18

(5.6)

19

(5.8)

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