Pharmacodynamics properties

• Pharmacotherapeutic Group
  Bile acid preparations
• Mechanism of Action
  The mechanism of action of UDCA in liver and cholestatic disorders has not yet been explained totally. However, UDCA alters bile acid composition, resulting in increases in the concentration of UDCA and decreases in the concentrations of the more hydrophobic and potentially toxic bile acids, cholic and chenodeoxycholic acids. UDCA also has a choleretic effect, resulting in increased bile acid output and bile flow. There is some evidence for immunological effects, including a reduction of abnormal expression of HLA Class I antigens on hepatocytes and a suppression of immunoglobulin and cytokine production. The Ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

Pharmacokinetic Properties

About 90% of the therapeutic dose of the Ursodeoxycholic acid is rapidly absorbed in the small intestine after oral administration. After the absorption, Ursodeoxycholic acid is absorbed in the liver (there is a substantial "first-pass-effect"), where it is conjugated with glycine or taurine and then secreted into the bile ducts. Only a small portion of Ursodeoxycholic acid is found in the systemic circulation.
This is excreted renally. With the exception of conjugation, Ursodeoxycholic acid is not metabolized. However, a small fraction of orally administered Ursodeoxycholic acid undergoes bacterial conversion to 7-keto-lithocholic acid resp. lithocholic acid after each enterohepatic circulation, while bacterial deconjugation also takes place in the duodenum. Ursodeoxycholic acid, 7-keto-lithocholic acid and lithocholic acid are relatively poorly soluble in water, so a large part of it is excreted via the bile into the faeces. Resorbed Ursodeoxycholic acid is conjugated again by the liver; 80% of the lithocholic acid formed in the duodenum is excreted in the faeces, but the remaining 20% of it are sulphated by the liver to insoluble lithocholylconjugates after absorption, which in turn are excreted via the bile and faeces.
Resorbed 7-keto-lithocholic acid is reduced to chenodeoxycholic acid in the liver.Lithocholic acid can cause cholestatic liver damage, when the liver is unable to sulphate the lithocholic acid. Although a reduced capacity to sulphate the lithocholic acid in the liver is found in somepatients, there is for the time being no clinical evidences that cholestatic liver damage can be associated with the therapy using Ursodeoxycholic acid. After repeated dosage, the Ursodeoxycholic acid concentration in the bile reaches a "steady state" after approximately 3 weeks: the total concentration of the Ursodeoxycholic acid, however, is never higher than about 60% of the total concentration of the bile acid in the bile: also at high doses. After therapy with Ursodeoxycholic acid is stopped, the concentration of Ursodeoxycholic acid in bile decreases quickly after 1 week to 5-10% of the "steady-state" concentration. The biological half-life of Ursodeoxycholic acid is approximately 3.5 to 5.8 days

Ursodex tablets should not be used concurrently with colestyramine, colestipol, or an antacid, on the basis of aluminium hydroxide and/or smectite (aluminium oxide), because these preparations bind Ursodex in the intestine and thereby inhibits its absorption and efficacy. If the use of such a medicine is necessary, must it be taken at least 2 hours before or after Ursodex. Ursodex may affect the absorption of ciclosporin from the intestine. In patients treated with ciclosporin the blood level of ciclosporin should be monitored and the ciclosporin dose should be adjusted, if necessary. In isolated cases Ursodex can reduce the absorption of ciprofloxacin.
Ursodex has been shown to reduce the peak plasma concentration (Cmax) and the AUC of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring of the outcome of concurrent use of nitrendipine and Ursodex is recommended. An increase of the dose of nitrendipine may be necessary. An interaction with a reduction of the therapeutic effect of dapsone was also reported. These observations, together with in vitro findings could be an indication that Ursodex can induce cytochrome P450 3A enzymes. Induction has, however not been observed in a well-designed interaction study with budesonide, which is a known cytochrome P450 3A substrate. Oestrogens and blood cholesterol lowering agents such as clofibrate increase hepatic cholesterol secretion and May therefore encourage biliary lithiasis; which is a counter-effect to Ursodex used for dissolution of gallstones.

• The dissolution of cholesterol stones in patients:
  • With one or more X-ray radiolucent (X-ray negative) gallstones, preferably with a diameter of not more than 2 cm, in a well-functioning gall bladder.
  • Refusing a surgical procedure or in which surgical intervention is not indicated.
  • With whom an oversaturation of cholesterol has been shown by chemical analysis of the bile produced by duodenum drainage.
• Primary Biliary Cholangitis.
• Hepatobiliary disorder associated with cystic fibrosis in children aged 6 years to 18 years.

Dosage:

The dosage should be calculated based on the patient's body weight. The calculated dosage should be rounded to the nearest number of tablets.
 

Dissolving of cholesterol stones:

Usual dosage: 8 to 10 mg/kg/day. The daily dose can be administered two or three times after the meals: two tablets should always be taken after the evening meal. Preferably, this single dose should be taken one hour before bedtime and ± two hours after the evening meal with a glass of milk or a small snack.
 

Primary Biliary Cholangitis:

The dosage of Ursodex in primary biliary cholangitis (stages I-III), amounts to 12-15 mg/kg/day, which is equivalent to four to eight tablets of 150 mg, two to four tablets of 300 mg, to be taken in two to three portions during the day, or with two tablets of 450 mg, to be taken in two portions during the day. The dosage of Ursodex in primary biliary cholangitis stage IV and an increase of the serum bilirubin contents (> 40 μg/l), should be in the first instance, only a half of the normal dose (6 to 8 mg/kg/day).
 

Pediatric population:

Children with cystic fibrosis aged 6 years to 18 years: Treatment of Hepatobiliary diseases as a result of cystic fibrosis 20 mg/kg/day divided in two to three divided doses. If necessary, increase to 30 mg/kg/day. This corresponds with four to ten tablets of 150mg, two to five tablets of 300 mg, or with two to three tablets of 450 mg, to be taken in one or two portions during the day.
 

Method of administration:

The Tablets should be swallowed whole with some liquid.

The following adverse reactions have been reported during clinical trials and are ranked using the following frequency: very common (greater than or equal to 1/10); common (greater than or equal to 1/100 to less than 1/10); uncommon (greater than or equal to 1/1,000 to less than 1/100); rare (greater than or equal to 1/10,000 to less than 1/1,000); very rare (greater than to 1/10,000); not known (cannot be estimated from the available data).
Gastrointestinal disorders: Pasty stools or diarrhea during treatment with Ursodex was common. In very rare cases, severe right upper abdominal pain has occurred during the treatment of primary biliary cholangitis.
Hepatobiliary disorders: During treatment with Ursodex calcification of gallstones can occur in very rare cases. During the treatment of advanced stages of primary biliary cholangitis decompensation of cirrhosis has been observed in very rare cases, which partially regressed after treatment discontinuation. Hypersensitivity reactions: Very rarely urticaria may occur.

Ursodex tablets should be taken under medical supervision. During the first three months of the treatment liver function parameters AST (SGOT), ALT (SGPT) and γ-GT should be monitored by the physician every 4 weeks, thereafter every 3 months. Apart from allowing for identification of responders and non-responders in patients being treated for primary biliary cholangitis, this monitoring would also enable an early detection of potential hepatic deterioration, particularly in patients with advanced primary biliary cholangitis.
When used for dissolving gallstones:
In order to be able to assess the therapeutic progression of the dissolution of gallstones and to timely identify a possible calcification of the stones, the gall bladder, depending on the size of the stones, should be visualized 6 to 10 months after the start of the treatment (oral cholecystography) with total image and occlusions and in the standing and lying position (ultrasound investigation).
If the gallbladder cannot be visualized on X-rays, or in cases of calcified gallstones, impaired contractility of the gall bladder or frequent episodes of biliary colic, the treatment with Ursodex should be discontinued.

• When used for the treatment of advanced primary biliary cholangitis:
  • In very rare cases decompensation of liver cirrhosis is observed which partially decreased after treatment discontinuation.
  • In patients with PBC, the clinical symptoms may worsen in rare cases at the start of treatment, e.g. pruritus may increase. In this case, the therapy is to be continued with a dose reduction and subsequently should be gradually increased to the recommended dose.
  • If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea.
  • Female patients who use Ursodex for dissolving gall stones must use an effective non-hormonal method of contraception, since hormonal contraception may increase biliary lithiasis.
• Pregnancy:
  • Ursodex must not be used during pregnancy, unless clearly necessary.
• Women of childbearing potential:
  • The possibility of a pregnancy must be excluded before beginning treatment .reliable contraception non-hormonal contraceptives or oral contraceptives with low oestrogen dose are recommended.
• Breastfeeding:
  • Breastfeeding women milk levels of Ursodeoxycholic acid levels in milk are very low and probably no adverse reactions are to be expected in breastfed infants.
• Fertility:
  • Animal studies did not show an influence of Ursodeoxycholic acid on fertility Human data on fertility treatment with Ursodex are not available.

Ursodex tablets should not be used in patients with:

• Acute inflammation of the gall bladder or bile ducts.
• Occlusion of the biliary tract (occlusion of the common bile duct or a cystic duct).
• Frequent episodes of biliary colic.
• X-ray radiolucent calcified gallstones.
• Impaired contractility of the gallbladder.
• Hypersensitivity to bile acids or to any of the excipient.
• Active gastric and duodenal ulcers.