4.1. Therapeutic indications

Treatment of primary biliary cholangitis (PBC) and for the dissolution of radiolucent gallstones in patients with a functioning gall bladder

Paediatric population

Hepatobiliary disorders associated with cystic fibrosis in children aged 1 month to 18 years.

4.2. Posology and method of administration

Posology

There are no age restrictions on the use of ursodeoxycholic acid in the treatment of PBC and for the dissolution of radiolucent gallstones. The following daily dose is recommended for the various indications:

For the treatment of primary biliary cholangitis (PBC)

The daily dose depends on body weight and is approximately 14 ± 2 mg UDCA per kg of body weight.

For the first 3 months of treatment, this medicinal product should be taken divided over the day. When the liver function parameters improve, the daily dose can be administered once a day in the evening.

Body weight

(kg)

Daily dose

(mg/kg BW)

Amount of Suspension (ml)*

First 3 months

Subsequently

Morning

Midday

Evening

Evening

(1 x daily)

8 – 11

12 – 16

-

1.25 ml

1.25 ml

2.5 ml

12 – 15

12 – 16

1.25 ml

1.25 ml

1.25 ml

3.75 ml

16 – 19

13 – 16

2.5 ml

-

2.5 ml

5 ml

20 – 23

13 – 15

1.25 ml

2.5 ml

2.5 ml

6.25 ml

24 – 27

13 – 16

2.5 ml

2.5 ml

2.5 ml

7.5 ml

28 – 31

14 – 16

1.25 ml

2.5 ml

5 ml

8.75 ml

32 – 39

12 – 16

2.5 ml

2.5 ml

5 ml

10 ml

40 – 47

13 – 16

2.5 ml

5 ml

5 ml

12.5 ml

48 – 62

12 – 16

5 ml

5 ml

5 ml

15 ml

63 – 80

12 – 16

5 ml

5 ml

10 ml

20 ml

81 – 95

13 – 16

5 ml

10 ml

10 ml

25 ml

96 – 115

13 – 16

10 ml

10 ml

10 ml

30 ml

Over 115

-

10 ml

10 ml

15 ml

35 ml

This medicinal product should be taken in accordance with the dosage regimen given above. The oral suspension must be taken regularly.

The use of ursodeoxycholic acid in PBC may be continued indefinitely.

For dissolution of cholesterol gallstones:

Approximately 10 mg of UDCA per kg of body weight daily, equivalent to:

Body Weight (kg)

Amount of Suspension (ml)*

5 – 7

1.25 ml

8 – 12

2.50 ml

13 – 18

3.75 ml

19 – 25

5 ml

26 – 35

7.5 ml

36 – 50

10 ml

51 – 65

12.5 ml

66 – 80

15 ml

81 – 100

20 ml

Over 100

25 ml

The suspension should be taken in the evening at bedtime. The oral suspension must be taken regularly.

The time required for dissolution of gallstones is likely to range from 6 to 24 months depending on stone size and composition.

Follow-up cholecystograms or ultrasound investigation may be useful at 6 month intervals until the gallstones have disappeared.

Treatment should be continued until 2 successive cholecystograms and/or ultrasound investigations 4-12 weeks apart have failed to demonstrate gallstones. This is because these techniques do not permit reliable visualisation of stones less than 2mm in diameter. The likelihood of recurrence of gallstones after dissolution by bile acid treatment has been estimated as up to 50% at 5 years. The efficiency of ursodeoxycholic acid in treating radio-opaque or partially radio-opaque gallstones has not been tested but these are generally thought to be less soluble than radiolucent stones. Non-cholesterol stones account for 10-15% of radiolucent stones and may not be dissolved by bile acids.

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

Cholesterol rich gallstones and PBC are very rare in children but when they occur, dosage should be related to bodyweight. There are no adequate data on the efficacy and safety in this population.

Hepatobiliary disorders associated with cystic fibrosis

Paediatric population

Children with cystic fibrosis aged 1 month to 18 years: 20 mg/kg/day in 2-3 divided doses, with a further increase to 30 mg/kg/day if necessary.

Very rarely, children under 10 kg body weight are affected. In this case, a commercially available oral syringe should be used. Please note: a syringe is not provided in the pack.

Up to 10 kg body weight: Dosing 20 mg UDCA/kg/day

Measuring device: 2 ml graduated oral syringe (not provided)

Body weight (kg)

Amount of Suspension (ml)*

Morning

Evening

4

0.8

0.8

4.5

0.9

0.9

5

1.0

1.0

5.5

1.1

1.1

6

1.2

1.2

6.5

1.3

1.3

7

1.4

1.4

7.5

1.5

1.5

8

1.6

1.6

8.5

1.7

1.7

9

1.8

1.8

9.5

1.9

1.9

10

2.0

2.0

More than 10 kg body weight (BW): Dosing 20-25 mg UDCA/kg/day

Measuring device: Measuring spoon

Body weight (kg)

Daily dose UDCA

(mg/kg BW)

Amount of Suspension (ml)*

Morning

Evening

11 – 12

21 – 23

2.5 ml

2.5 ml

13 – 15

21 – 24

2.5 ml

3.75 ml

16 – 18

21 – 23

3.75 ml

3.75 ml

19 – 21

21 – 23

3.75 ml

5 ml

22 – 23

22 – 23

5 ml

5 ml

24 – 26

22 – 23

5 ml

6.25 ml

27 – 29

22 – 23

6.25 ml

6.25 ml

30 – 32

21 – 23

6.25 ml

7.5 ml

33 – 35

21 – 23

7.5 ml

7.5 ml

36 – 38

21 – 23

7.5 ml

8.75 ml

39 – 41

21 – 22

8.75 ml

8.75 ml

42 – 47

20 – 22

8.75 ml

10 ml

48 – 56

20 – 23

11.25 ml

11.25 ml

57 – 68

20 – 24

13.75 ml

13.75 ml

69 – 81

20 – 24

16.25 ml

16.25 ml

82 – 100

20 – 24

20 ml

20 ml

>100

-

22.5 ml

22.5 ml

* Conversion table:

Amount of Suspension

Ursodeoxycholic Acid

5 ml

250 mg

3.75 ml

187.5 mg

2.5 ml

125 mg

1.25 ml

62.5 mg

Method of administration

Oral use.

Shake well before use.

A 5ml measuring spoon with graduations of 1.25 ml, 2.5 ml, 3.75 ml and 5 ml is provided and can be used to deliver the majority of doses e.g. 6.25 ml is given as 1 x 5 ml and 1 x 1.25 ml and 8.75 ml is given as 1 x 5 ml and 1 x 3.75 ml. A measuring cup or oral syringe (not supplied) can also be used if available.

Doses under 2 ml for children with cystic fibrosis weighing under 10 kg should be administered with a 2 ml oral syringe (not supplied).

If necessary, this medicinal product can be administered via a gastric, duodenal or nasal feeding tube (see section 6.6). It is advised to rinse medium / larger bore tubes e.g. Fr14, twice with at least 10 ml of water following administration and to rinse smaller bore tubes e.g. Fr4, at least once with a minimum of 3 ml of water.

4.3. Contraindications

DEOXXA should not be used in patients with:

• Hypersensitivity to the active substance, bile acids 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 cystic duct)

• Frequent episodes of biliary colic

• Radio-opaque calcified gallstones

• Impaired contractility of the gall bladder

When used in hepatobiliary disorders associated with cystic fibrosis in children aged 1 month to 18 years:

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

4.4. Special warnings and precautions for use

This medicinal product 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 PBC, this monitoring would also enable early detection of potential hepatic deterioration, particularly in patients with advance stage PBC.

When used for treatment of advanced stage of primary biliary cholangitis:

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

In patients with PBC, in rare cases the clinical symptoms may worsen at the beginning of treatment, e.g. the itching may increase. In this case the dose of ursodeoxycholic acid should be reduced to 250 mg daily and then gradually increased to the recommended dose described in section 4.2.

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

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, this medicinal product should not be used.

Female patients taking ursodeoxycholic acid for dissolution of gallstones should use an effective non-hormonal method of contraceptive, since hormonal contraceptives may increase biliary lithiasis (see section 4.5 and 4.6)

This medicinal product contains 7.5 mg benzoic acid in each 5 ml of suspension. Benzoic acid may increase jaundice in neonates.

This medicinal product contains 51.75 mg propylene glycol in each 5 ml of suspension. May induce serious adverse effects in neonates.

This medicinal product contains 1600 mg xylitol in each 5 ml of suspension. May have a laxative effect. Calorific value 2.4 kcal/g xylitol.

This medicinal product contains 1.5 mg alcohol (ethanol) in each 5 ml of suspension which is equivalent to 0.03% w/v. The amount in each 5 ml dose of this medicine is equivalent to less than 1 ml of beer or wine. The small amount of alcohol in this medicine will not have any noticeable effects.

This medicinal product contains 11.07 mg sodium per 5 ml of suspension, equivalent to 0.6 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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

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 this medicinal product.

Ursodeoxycholic acid 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, ursodeoxycholic acid can reduce the absorption of ciprofloxacin.

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

Ursodeoxycholic acid has been shown to reduce the peak plasma concentrations (Cmax) and area under the curve (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 in 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 indicate a potential for ursodeoxycholic acid to 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.

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

Pregnancy

There are no or limited amounts of data on the use of ursodeoxycholic acid in pregnant women. Studies in animals have shown reproductive toxicity during the early phase of gestation (see section 5.3). Ursodeoxycholic acid must not be used during pregnancy unless clearly necessary.

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.

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

Breast-feeding

According to few documented cases of breast-feeding women, milk levels of ursodeoxycholic acid are very low and probably no adverse reactions are to be expected in breast-fed infants.

Fertility

Animal studies did not show an influence of ursodeoxycholic acid on fertility (see section 5.3). Human data on fertility effects following treatment with ursodeoxycholic acid are not available.

4.7. Effects on ability to drive and use machines

Ursodeoxycholic acid 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:

In clinical trials, reports of pasty stools or diarrhoea during ursodeoxycholic acid therapy were common.

Very rarely, severe right upper abdominal pain has occurred during the treatment of primary biliary cirrhosis.

Hepatobiliary disorders:

During treatment with ursodeoxycholic acid, calcification of gallstones can occur in very rare cases.

During therapy of the advanced stages of primary biliary cirrhosis, in very rare cases decompensation of hepatic cirrhosis has been observed, which partially regressed after the treatment was discontinued.

Skin and subcutaneous disorders:

Very rarely, urticaria can 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 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.

Additional information on special populations:

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