SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ursogal Tablets 150mg /

Ursodeoxycholic Acid Tablets 150mg.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Ursodeoxycholic acid (UDCA) Ph. Eur. 150mg per tablet.

Excipient(s) with known effect: 98mg of lactose per tablet.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablets.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Dissolution of radiolucent cholesterol-rich gallstones in patients with a functioning gallbladder.

4.2    Posology and method of administration

For oral administration.

A daily dose of 8-10mg/kg (3 or 4 tablets of UDCA 150mg per day for most patients) is recommended. This should be taken in two divided doses after meals, with at least half the dose being taken after the evening meal.

The time required for dissolution of gallstones is generally in the range of 6-24 months, and is dependent on the size and composition of the stones.

Treatment should be regularly monitored (by cholecystograms) and continued for 3-4 months following the disappearance of the gallstones. Stones may recur after successful treatment. The time required to effect stone dissolution may be increased if UDCA is temporarily discontinued (for 3-4 weeks) during treatment.

The dose of UDCA for elderly patients and for children should be related to body weight (8-10mg/kg/day). Obese patients may require a higher dose of UDCA (up to 15mg/kg/day).

4.3.    Contraindications

UDCA should not be used in patients with:

-    acute inflammation of the gall bladder or biliary tract

-    occlusion of the biliary tract (occlusion of the common bile duct or a cystic duct)

-    frequent episodes of biliary colic

-    impaired contractility of the gall bladder.

UDCA is not suitable for the dissolution of radio-opaque calcified gallstones.

UDCA should not be used in patients who are pregnant, or may become pregnant.

UDCA should not be used in patients with active gastric or duodenal ulcers, or with intestinal or hepatic disorders which interfere with the enterohepatic circulation of bile acids e.g. ileal resection and stoma, regional ileitis, extra and intrahepatic cholestasis, severe, acute and chronic liver diseases.

Ursogal Tablets 150mg should not be used in patients with a known hypersensitivity to UDCA or the tablet excipients.

4.4.    Special warnings and precautions for use

UDCA should be taken under medical supervision.

During the first three months of treatment, the liver function parameters AST (SGOT), ALT (SGPT) and y-GT should be monitored by the physician every four weeks, thereafter every three months.

When used for the dissolution of cholesterol gallstones:

In order to assess therapeutic progress and for timely detection of any calcification of the gallstones, depending on stone size, the gall bladder should be visualised (oral cholecystography) with overview and occlusion views in standing and supine positions (ultrasound control) six to ten months after the beginning of treatment.

If the gall bladder cannot be visualised on X-ray images, or in cases of calcified gallstones, impaired contractility of the gall bladder or frequent episodes of biliary colic, UDCA should not be used.

Female patients taking UDCA for dissolution of gallstones should use an effective non-hormonal method of contraception, since hormonal contraceptives may increase biliary lithiasis (see sections 4.5. and 4.6.).

If diarrhoea occurs, the dose must be reduced and in cases of persistent diarrhoea, the therapy should be discontinued.

Excessive dietary intake of calories and cholesterol should be avoided.

This product contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5.    Interaction with other medicinal products and other forms of interaction

UDCA should not be administered concomitantly with colestyramine, colestipol, charcoal or antacids containing aluminium hydroxide and/or smectite (aluminium oxide), because these preparations bind UDCA in the intestine and thereby inhibit its absorption and efficacy. Should the use of a preparation containing one of these substances be necessary, it must be taken at least two hours before or after UDCA.

UDCA can affect the absorption of ciclosporin from the intestine. In patients receiving ciclosporin treatment, blood concentrations of this substance should therefore be checked by the physician and the ciclosporin dose adjusted if necessary.

In isolated cases UDCA can reduce the absorption of ciprofloxacin.

In a clinical study in healthy volunteers concomitant use of UDCA (500mg/day) and rosuvastatin (20mg/day) resulted in slightly elevated plasma levels of rosuvastatin. The clinical relevance of this interaction also with regard to other statins is unknown.

There is a potential for UDCA to induce cytochrome P450 3A enzymes as indicated by a report of an interaction with a reduction of the therapeutic effect of dapsone, as well as in vitro findings. Induction has, however, not been observed in a well-designed interaction study with budesonide, which is a known cytochrome P450 3A substrate.

Estrogenic hormones, estrogen rich oral contraceptives and blood cholesterol lowering agents such as clofibrate increase hepatic cholesterol secretion and may therefore encourage biliary lithiasis, which is a counter-effect to UDCA used for dissolution of gallstones.

4.6.    Fertility, pregnancy and lactation

Animal studies did not show an influence of UDCA on fertility. Human data on fertility effects following treatment with UDCA are not available.

There are no or limited amounts of data from the use of UDCA in pregnant women. Studies in animals have shown reproductive toxicity during gestation (see section 5.3). UDCA is contraindicated in pregnancy (see section 4.3). Women of childbearing potential should be treated only if they are using reliable contraception; non-hormonal or low-oestrogen oral contraceptive measures are recommended. However, in patients taking UDCA for dissolution of gallstones, effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis.

The possibility of a pregnancy must be excluded before beginning treatment.

According to few documented cases of breastfeeding women, milk levels of UDCA are very low and probably no adverse reactions are to be expected in breastfed infants.

4.7.    Effects on ability to drive and use machines

UDCA has no or negligible influence on the ability to drive and use machines.

4.8.    Undesirable effects

The evaluation of undesirable effects is based on the following frequency data:

Very common (> 1/10)

Common (> 1/100 to < 1/10)

Uncommon (> 1/1,000 to < 1/100)

Rare (> 1/10,000 to < 1/1,000)

Very rare / Not known (< 1/10,000 / cannot be estimated from available data)

Gastrointestinal disorders
Common	Reports of pasty stools or diarrhoea in clinical trials
Hepatobiliary disorders
Very rare	Calcification of gallstones
Skin and subcutaneous tissue disorders
Very rare	Urticaria

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9. Overdose

Diarrhoea may occur in cases of overdose. In general, other symptoms of overdose are unlikely because the absorption of UDCA decreases with increasing dose and therefore more is excreted with the faeces.

No specific counter-measures are necessary and the consequences of diarrhoea should be treated symptomatically with restoration of fluid and electrolyte balance. However, ion-exchange resins may be used to bind bile acids in the intestines. It is recommended that liver function tests are monitored.

Additional information on special populations:

Long-term, high-dose UDCA therapy (28-30 mg/kg/day) in patients with primary sclerosing cholangitis (off-label use) was associated with higher rates of serious adverse events.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

UDCA is a bile acid, normally only present as a very small proportion (up to 5%) of the total biliary bile acids. Oral administration of UDCA increases this fraction in a dose-related manner and UDCA may become the major biliary bile acid (40-50%). UDCA decreases biliary lipid cholesterol secretion, mainly due to a reduction in the absorption of cholesterol from the intestine. There appear to be no effects on cholesterol or bile acid biosynthesis. Cholesterol is gradually solubilised from the gallstones.

5.2 Pharmacokinetic properties

UDCA is detected in plasma within 10-40 minutes of oral administration. UDCA is only moderately soluble in the upper small intestine but is well absorbed in the jejeunum and ileum. Peak levels are seen at approximately 1 and 3 hours. UDCA shows hepatic first pass clearance of approximately 60% (conjugation is predominantly with glycine). UDCA is rapidly excreted into bile. Glycine-conjugated UDCA may be hydrolysed to free UDCA. That which is not absorbed undergoes bacterial conversion to lithocholic acid, the main bacterial degradation product which is poorly absorbed into bile.

Another metabolite, 7-ketolithocholic acid may be reabsorbed and transformed in the liver to UDCA and lithocholic acid. UDCA and its metabolites are excreted in the faeces.

Preclinical safety data

A similar drug to UDCA has been found to be carcinogenic in animals. The relevance of these findings to the clinical use of UDCA has not been established. Embryotoxicity associated with the use of UDCA has been observed in rabbits so UDCA is contra-indicated in pregnancy.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose BP

Microcrystalline cellulose (50 micron) BP Magnesium stearate BP

6.2    Incompatibilities

Not applicable

6.3    Shelf life

Polypropylene containers with polyethylene press-fit cap: 24 months from the date of manufacture.

PVC blister strip 250^m thick backed by 20^ aluminium foil: 18 months from the date of manufacture.

6.4    Special precautions for storage

Store at room temperature (below 25 °C).

6.5    Nature and contents of container

Round, white, uncoated, scored tablets marked UDCA 150mg contained within polypropylene tablet containers with polyethylene press-fit cap or PVC blister strip 250pm thick backed by 20pm aluminium foil.

Pack sizes: 3, 4, 9, 12, 21, 28, 30, 56, 60, 84, 90, 100, 112, 120, 250 and 500 tablets.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Galen Limited

Seagoe Industrial Estate

Craigavon

BT63 5UA

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 27827/0015.

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 06 August 1997.

10 DATE OF REVISION OF THE TEXT

04/12/2013