Ursodeoxycholsäure: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

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 | Placebo
| 8 - 10 mg/kg/day |
| (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 | (5.0)
Infection Viral | 30 | (19.4) | 41 | (25.8)
Digestive System | | | |
Abdominal Pain | 67 | (43.2) | 70 | (44.0)
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 | (5.0)
Nausea | 22 | (14.2) | 27 | (17.0)
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 | (5.0)
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 | (11.0) | 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 | (9.0) | 29 | (8.9)
Influenza-like Symptoms | 21 | (6.5) | 19 | (5.8)
Digestive System | | | |
Abdominal Pain | 20 | (6.2) | 39 | (12.0)
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 | (24.0)
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)

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 vitroand 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 co-administered 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

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 4 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.

Neither accidental nor intentional overdosing with ursodiol has been reported. Doses of ursodiol in the range of 16 - 20 mg/kg/day have been tolerated for 6 to 37 months without symptoms by 7 patients. The LD ₅₀for ursodiol in rats is over 5000 mg/kg given over 7 to 10 days and over 7500 mg/kg for mice. The most likely manifestation of severe overdose with ursodiol would probably be diarrhea, which should be treated symptomatically.

About 90% of a therapeutic dose of ursodiol is absorbed in the small bowel after oral administration. After absorption, ursodiol enters the portal vein and undergoes efficient extraction from portal blood by the liver (i.e., there is a large “first-pass” effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodiol in bile is concentrated in the gallbladder and expelled into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions provoked by physiologic responses to eating. Only small quantities of ursodiol appear in the systemic circulation and very small amounts are excreted into urine. The sites of the drug’s therapeutic actions are in the liver, bile, and gut lumen.

Beyond conjugation, ursodiol is not altered or catabolized appreciably by the liver or intestinal mucosa. A small proportion of orally administered drug undergoes bacterial degradation with each cycle of enterohepatic circulation. Ursodiol can be both oxidized and reduced at the 7-carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, there is some bacterially catalyzed deconjugation of glyco- and tauro- ursodeoxycholic acid in the small bowel. Free ursodiol, 7-keto-lithocholic acid, and lithocholic acid are relatively insoluble in aqueous media and larger proportions of these compounds are lost from the distal gut into the feces. Reabsorbed free ursodiol is reconjugated by the liver. Eighty percent of lithocholic acid formed in the small bowel is excreted in the feces, but the 20% that is absorbed is sulfated at the 3-hydroxyl group in the liver to relatively insoluble lithocholyl conjugates which are excreted into bile and lost in feces. Absorbed 7-keto-lithocholic acid is stereospecifically reduced in the liver to chenodiol.

Lithocholic acid causes cholestatic liver injury and can cause death from liver failure in certain species unable to form sulfate conjugates. Lithocholic acid is formed by 7-dehydroxylation of the dihydroxy bile acids (ursodiol and chenodiol) in the gut lumen. The 7-dehydroxylation reaction appears to be alpha-specific, i.e., chenodiol is more efficiently 7-dehydroxylated than ursodiol and, for equimolar doses of ursodiol and chenodiol, levels of lithocholic acid appearing in bile are lower with the former. Man has the capacity to sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals, but such a deficiency has not yet been clearly demonstrated.

Pharmacodynamics

Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.