1. 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.

2. Primary Biliary Cholangitis.

Paediatric population

3. 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, corresponding to, for example, four to six 150 mg tablets, or two to three tablets of 300 mg, or two tablets of 450 mg. The daily dose can be administered two or three times after the meals: two tablets should always be taken after the evening meal.

Also a single evening dose can be selected (e.g., a patient of 60 kg, in the evening two tablets of 300 mg). 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.

The duration of the treatment in order to obtain lysis of the gallstones depends on their size, but is usually not shorter than three to four months. To assess the result of the therapy properly, it is necessary to determine the size of the stones accurately at the start of the treatment and to check this further regularly, for example every six months, by means of a new contrast X-ray recording and/or sonographic recording.

In patients in whom, after six months of treatment with the indicated dosage, the stones are not reduced in size, it is recommended to determine the lithogenic index in the bile by means of a duodenum drainage. When the bile has an index of > 1.0, it is unlikely that a favourable result can be obtained, and it is better to consider a different form of treatment for the gallstones.

Treatment should be continued for three to four months after it is established by means of ultrasound check that the gallstones are completely dissolved. An interruption of the treatment for three to four weeks results in a return to over-saturation of the bile and prolongs the overall duration of the therapy. The interruption of the treatment after the dissolving of the gallstones can be followed by a recurrence.

Primary Biliary Cholangitis

The dosage of ursodeoxycholic acid 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 ursodeoxycholic acid in primary biliary cholangitis stage IV and an increase of the serum bilirubin contents (> 40 μ g/l), should be in the first instance, only a half of the normal dose (6 to 8 mg/kg/day). Thereafter, the liver function should be closely monitored for several weeks (once every two weeks for six weeks). If there is no deterioration of the liver function (AF, ALT (SGPT), AST (SGOT), γ -GT, bilirubin) and no increase in itching occurs, the dose may be further increased to the usual level. Moreover, the liver function must then again be closely monitored for several weeks. If again no deterioration of the liver function takes place, the patient may be held at the normal dosage for a long time.

In patients with primary biliary cholangitis stage IV without elevated serum bilirubin, the usual starting dose is allowed to be administered directly. Anyway, here too an accurate control of the liver function should be executed.

The treatment of the primary biliary cholangitis should be regularly assessed on the basis of liver values (laboratory) and clinical findings.

Paediatric 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

If the patient has difficulty in swallowing because of the size of the tablet, the tablet can be halved if necessary on the dividing score, so that one half tablet can be taken twice directly in sequence.

Ursodeoxycholic acid 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 listed in section 6.1.

- Active gastric and duodenal ulcers;

Paediatric population

- Unsuccessful portoenterostomy or without recovery of good bile flow in children with biliary atresia.

Ursodeoxycholic acid 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 Ursodeoxycholic acid 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 as described in section 4.2.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea.

Female patients who use Ursodeoxycholic acid for dissolving gall stones must use an effective non-hormonal method of contraception, since hormonal contraception may increase biliary lithiasis (see sections 4.5 and 4.6).

Ursodeoxycholic acid 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 ursodeoxycholic acid 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 Ursodeoxycholic acid.

Ursodeoxycholic acid 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 Ursodeoxycholic acid can reduce the absorption of ciprofloxacin.

In a clinical study in healthy volunteers, the concomitant use of UDCA (500 mg/day) and rosuvastatin (20 mg/day) resulted in slightly elevated plasma levels of rosuvastatin.The clinical relevance of this interaction, also with other statins, is not known.

Ursodeoxycholic acid has been shown to reduce the peak plasma concentration (C_max) and the AUC of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring of the outcome of concurrent use of nitrendipine and ursodeoxycholic acid 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 ursodeoxycholic acid 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 ursodeoxycholic acid used for dissolution of gallstones.

Pregnancy

There are no or limited amount of data from the use of ursodeoxycholic acid in pregnant women. Studies in animals have shown reproductive toxicity during the early gestation phase (see section 5.3).

Ursodeoxycholic acid must not be used during pregnancy, unless clearly necessary.

Women of childbearing potential

Women of childbearing potential should be treated with ursodeoxycholic acid, only if they practice reliable contraception: non-hormonal contraceptives or oral contraceptives with low oestrogen dose are recommended. However, in patients taking Ursodeoxycholic acid for dissolving gallstones an 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.

Breastfeeding

According to few documented cases of 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 (see section 5.3). Human data on fertility treatment with ursodeoxycholic acid are not available.

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

The following adverse reactions have been reported during clinical trials and are ranked using the following frequency:

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 (<1/10,000);

not known (cannot be estimated from the available data).

Gastrointestinal disorders:

In clinical studies, reports of pasty stools or diarrhoea during treatment with ursodeoxycholic acid were common.

In very rare cases, severe right upper abdominal pain has occurred during the treatment of primary biliary cholangitis.

Hepatobiliary disorders:

During treatment with ursodeoxycholic acid 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.

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.co.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the case of overdose diarrhoea may occur. In general, other symptoms of overdose are unlikely, because the absorption of the ursodeoxycholic acid decreases with increasing dose and therefore more is excreted in the faeces.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea.

No specific measures are needed and the consequences of diarrhoea should be treated symptomatically with restoration of fluid and electrolyte balance.

Additional information or special populations

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

Pharmacotherapeutic group: Bile acid preparations, ATC code: A05AA02

Bile acids are among the most important components of the bile and play a role in the stimulation of bile secretion. Bile acids are also important to keep the cholesterol in bile in solution. In a healthy person, the ratio between the concentration of cholesterol and bile acids in the bile is such that the cholesterol will remain in solution for most of the day. In this case, no gallstones can form (the bile is non-lithogenic). In patients with cholesterol stones in the bile, this ratio is changed and the bile is supersaturated with cholesterol (bile is lithogenic). This may cause a precipitation of cholesterol crystals and the formation of gallstones after some time.

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

Investigations of the effect of ursodeoxycholic acid on the cholestasis in patients with impaired biliary drainage and on the clinical symptoms in patients with primary biliary cholangitis and cystic fibrosis have shown that cholestatic symptoms in the blood (to be measured by the increased value of alkaline phosphatase (AF), gamma-GT and bilirubin) and the itch declined rapidly, while also the fatigue decreased in the majority of patients. Moreover, studies seem to indicate a positive benefit-risk ratio of the ursodeoxycholic acid in children and young adult cystic fibrosis patients with mild to moderate hepatobiliary disorders.

Paediatric population

Cystic fibrosis

From clinical reports long-term experience of 10 years and more has been gained with UDCA therapy in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can inhibit bile duct proliferation, can halt progression of histological damage and even reverse hepato-biliary changes, if it happens at an early stage of CFAHD. The treatment with UDCA should be started as soon as the CFAHD diagnosis is made, in order to optimize the effectiveness of the treatment.

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 metabolised. 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 some patients, there is for the time being no clinical evidence 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.

a) Acute toxicity

Acute toxicity studies in animals have not revealed any toxic damage.

b) Chronic toxicity

Subchronic toxicity studies in monkeys showed hepatotoxic effects in the groups given high doses, including functional changes (e.g. liver enzyme changes) and morphological changes such as bile duct proliferation, portal inflammatory foci and hepatocellular necrosis. These toxic effects are most likely attributable to lithocholic acid, a metabolite of ursodeoxycholic acid, which in monkeys – unlike humans – is not detoxified. Clinical experience confirms that the described hepatotoxic effects are of no apparent relevance in humans.

c) Carcinogenic and mutagenic potential

Long-term studies in mice and rats revealed no evidence of ursodeoxycholic acid having carcinogenic potential. In vitro and in vivo genetic toxicology tests with ursodeoxycholic acid were negative. The tests with ursodeoxycholic acid revealed no relevant evidence of a mutagenic effect.

d) Toxicity to reproduction

In studies in rats, tail malformations occurred after a dose of 2000 mg per kg of body weight.

In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mg per kg of body weight). ursodeoxycholic acid had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.

Cellulose microcrystalline (Microcel 101) (E460), Polyvinyl pyrrolidone (Plasdone K-90) (E1201), Magnesium Stearate (E572), Sodium Starch Glycolate Type A (Primojel).

Not applicable

24 months

Do not store above 25° C

Clear PVC/PVDC – plain aluminium foil.

Pack size: 20, 30, 50, 60 and 100 tablets.

Not all pack sizes may be marketed.

No special requirements.