4.1. Therapeutic indications

- Treatment of primary biliary cholangitis (PBC) in patients without decompensated cirrhosis.

- Dissolution of radiolucent cholesterol gallstones not larger than 15 mm in diameter in patients with a functioning gallbladder and for whom surgical treatment is not indicated.

- Paediatric population: Hepatobiliar disorder associated with cystic fibrosis in children aged 6 years to less than 18 years.

4.2. Posology and method of administration

Ursodeoxycholic acid Strides 250mg Capsules hard or Ursodeoxycholic acid 250mg Hard Capsules is called Ursodeoxycholic acid throughout the SmPC.

Posology

There are no age restrictions on the use of Ursodeoxycholic acid. For patients weighing less than 47 kg or patients who are unable to swallow Ursodeoxycholic acid, other formulations are available (suspension).

The following daily dose is recommended for the various indications:

Treatment of primary biliary cirrhosis (PBC)

Stage I-III

The daily dose is dependent on body weight and ranges from 3 to 7 capsules (12-16 mg -ursodeoxycholic acid per kg of body weight).

During the first 3 months of treatment, Ursodeoxycholic acid should be taken in divided doses throughout the day. If liver function improves, the total daily dose can be taken once daily in the evening.

Body weight

(kg)

Daily dose

(mg/kg body weight)

Ursodeoxycholic acid

First 3 months

Subsequently

Morning

Afternoon

Evening

Evening

(once daily)

47 – 62

12 – 16

1

1

1

3

63 – 78

13 – 16

1

1

2

4

79 – 93

13 – 16

1

2

2

5

94 – 109

14 – 16

2

2

2

6

More than 110

2

2

3

7

Stage IV:

In combination with increased serum bilirubin levels (> 40 μg/L; conjugated), only half the normal dosage should initially be given (see dosage for stages I - III), (6 – 8 mg ursodeoxycholic acid per kg body weight per day, equivalent to about 2 to 3 Ursodeoxycholic acid).

Thereafter, liver function should be closely monitored for several weeks (once every 2 weeks for 6 weeks). If there is no deterioration in liver function (AP, ALAT, ASAT, gamma-GT, bilirubin) and if no increased pruritus occurs, the dosage can be increased further to the usual level. However, liver function should again be closely monitored for several weeks. Once again, if there is no deterioration in liver function, the patient can be maintained at the normal dosage over the long term.

Patients with primary biliary cirrhosis (stage IV) without increased serum bilirubin levels are allowed to receive the normal starting dose immediately (see dosage stages I - III).

However, close monitoring of liver function, as described above, is likewise applicable in such cases; treatment of primary biliary cirrhosis will need to be regularly assessed on the basis of liver (laboratory) values and clinical findings.

Method of administration

For oral administration.

The capsules should be swallowed whole with some liquid. Care should be taken to ensure that they are taken regularly.

Dissolution of gallstones:

Adults: Approx. 10mg ursodeoxycholic acid (UDCA) per kg body weight per day according to:

- up to 60 kg: 2 capsules

- 61-80 kg: 3 capsules

- 81-100 kg: 4 capsules

- above 100 kg: 5 capsules

Method of administration

For oral administration.

The capsules should be swallowed whole with some liquid in the evening before bedtime. Care should be taken to ensure that they are taken regularly.

Based on experience to date, the duration of the dissolution process with Ursodeoxycholic acid is 6 months to 2 years, depending on the initial size of the stones. For a proper assessment of the therapeutic outcome, it is necessary, at the start of treatment, to accurately determine the size of the existing stones and subsequently to monitor them regularly, for example, every 3 to 4 months, via new X-rays and/or ultrasound scans.

In patients whose stones have not decreased in size after six months of treatment at the dosage stated, it is recommended that the biliary lithogenic index be determined via duodenal samples. If 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 gallstones. Treatment must be continued for 3 to 4 months after ultrasound follow-up has confirmed complete dissolution of the gallstones. Discontinuation of treatment for 3-4 weeks leads to a return of bile supersaturation and prolongs the overall duration of therapy. Discontinuation of treatment upon dissolution of the gallstones may be followed by a relapse.

Older people:

There is no evidence to suggest that any alteration in the adult dose is needed but the relevant precautions should be taken into account.

Paediatric population:

Children with cystic fibrosis aged 6 years to less than 18 years: 20 mg/kg/day in 2-3 divided doses, with a further increase to 30 mg/kg/day if necessary.

Body weight (kg)

Daily dose [mg/kg BW]

Ursodeoxycholic acid Strides 250 mg Hard Capsules

morning

afternoon

evening

20–29

17-25

1

-

1

30–39

19-25

1

1

1

40–49

20-25

1

1

2

50–59

21-25

1

2

2

60–69

22-25

2

2

2

70–79

22-25

2

2

3

80–89

22-25

2

3

3

90–99

23-25

3

3

3

100–109

23-25

3

3

4

over 110

3

4

4

4.3. Contraindications

Ursodeoxycholic acid should not be used in patients with:

• Hypersensitivity to active substance or to any of the excipients listed in Section 6.1

• 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

• Radio-opaque calcified gallstones

• Impaired contractility of the gall bladder

• Non functioning gall bladder

• Inflammatory bowel disease

• Hepatic and intestinal conditions interfering with enterohepatic recirculation of bile acids:

• extrahepatic cholestasis intrahepatic cholestasis

• ileal resection

• regional ileitis

• ileal stoma

• Acute, chronic or severe liver disease

• Active duodenal ulcer

• Active gastric ulcer

• Paediatric population: Unsuccessful portoenterostomy or without recovery of good bile flow in children with biliary atresia

4.4. Special warnings and precautions for use

Ursodeoxycholic acid should be taken under medical supervision.

During the first 3 months of 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 cirrhosis, this monitoring would also enable early detection of potential hepatic deterioration, particularly in patients with advanced stage primary biliary cirrhosis.

When used for 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) 6-10 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, Ursodeoxycholic acid should not be used.

Female patients taking ursodeoxycholic acid in order to dissolve gallstones should use effective non-hormonal contraceptives as hormonal oral-contraceptives may increase biliary lithiasis (see section 4.5 and 4.6)

When used for treatment of advanced stage of primary biliary cirrhosis(PBC):

In very rare cases decompensation of hepatic cirrhosis has been observed, which partially regressed after the treatment was discontinued.

In rare cases in patients with primary biliary cirrhosis the clinical symptoms may worsen at the beginning of treatment, e.g. the itching may increase. Should this occur, therapy should be reduced to 250 mg capsule daily, and the therapy gradually increased to the recommended daily dose, as described in section 4.2.“

Diarrhoea

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

Dietary intake of calories and cholesterol

Excessive dietary intake of calories and cholesterol should be avoided; a low cholesterol diet will probably improve the effectiveness of Ursodeoxycholic acid.

Information on sodium content

This medicine contains less than 1 mmol sodium (23 mg) per capsule, i.e. is essentially 'sodium-free'

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

Colestyramine, colestipol, antacids containing aluminium hydroxide and/or smectite Ursodeoxycholic acid should not be administered concomitantly with colestyramine, colestipol or antacids containing aluminium hydroxide and/or smectite (aluminium oxide), because these preparations bind ursodeoxycholic acid 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 2 hours before or after Ursodeoxycholic acid.

Charcoal

Charcoal may reduce the absorption of Ursodeoxycholic acid.

Ciclosporin

Ursodeoxycholic acid can increase 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.

Ciprofloxacin

In isolated cases Ursodeoxycholic acid can reduce the absorption of ciprofloxacin.

Nitrendipine

Ursodeoxycholic acid has been shown to reduce the plasma peak concentrations (Cmax) and the area under the curve (AUC) of the calcium antagonist nitrendipine. 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.

Rosuvastatin

In a clinical study in healthy volunteers concomitant use of Ursodeoxycholic acid (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.

Dapsone

An interaction with a reduction of the therapeutic effect of dapsone was also reported.

Cytochrome P450 3A enzymes

These observations together with in vitro findings could indicate a potential for ursodeoxycholic acid to induce cytochrome P450 3A enzymes. Controlled clinical trials have shown, however, that ursodeoxcholic acid does not have a relevant induction effect on cytochrome P450 3A enzymes.

Oestrogenic hormones and blood cholesterol lowering agents

Oestrogenic hormones 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.

4.6. Fertility, pregnancy and lactation

Animal studies did not show an influence of UDCA on fertility (see section 5.3).

Human data on fertility effects following treatment with UDCA are not available.

Fertility

Women of childbearing potential should be treated only if they use reliable contraception: non-hormonal or low-oestrogen oral contraceptive measures are recommended. However, in patients taking ursodeoxycholic acid for dissolution of gallstones, effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis.

Pregnancy

There are no adequate data on the use of ursodeoxycholic acid, particularly in the first trimester of pregnancy. Animal studies have provided evidence of a teratogenic effect during the early phase of gestation (see section 5.3, Toxicity to reproduction). Ursodeoxycholic acid must not be used during pregnancy unless clearly necessary.

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

Breast-feeding

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

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

4.8. Undesirable effects

System Organ Class

Frequency

Adverse Event

Gastrointestinal disorders

Common

Pasty stools or diarrhoea (reported from clinical trials)

Very rare

Severe right upper abdominal pain (during the treatment of primary biliary cholangitis)

Not known

Vomiting, nausea

Hepatobiliary disorders

Very rare

Calcification of gallstones, decompensation of hepatic cirrhosis1 (during therapy of the advanced stages of primary biliary cholangitis), which partially regressed after the treatment was discontinued.

Not known

Increase of the serologic levels of alkaline phosphatase, γ-GT and bilirubin (in patients with an advanced stage of PBC).

Skin and subcutaneous disorders

Very rare

Urticaria

Not known

Pruritus

1Observed during therapy of the advanced stages of PBC and which partially regressed after treatment was discontinued.

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 (< 1/10,000)

Not known (cannot be estimated from available data)

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Diarrhoea may occur in cases of overdose. In general, other symptoms of overdose are unlikely because the absorption of ursodeoxycholic acid 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 useful to bind bile acids in the intestine. Liver function tests monitoring is recommended.

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.