Ursofalk 250mg/5ml Suspension

5ml (= 1 measuring spoon) of Ursofalk Suspension contains 250mg of ursodeoxycholic acid as the active ingredient.

Suspension for oral administration.

Ursofalk 250mg/5ml Suspension is indicated in the treatment of primary biliary cirrhosis (PBC) and for the dissolution of radiolucent gallstones in patients with a functioning gall bladder

There are no age restrictions on the use of Ursofalk 250mg/5ml suspension. The following daily dose is recommended for the various indications:

For the treatment of primary biliary cirrhosis (PBC)

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

For the first 3 months of treatment, Ursofalk 250mg/5ml suspension 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.

*1 measuring spoonful (5ml oral suspension) contains 250mg of ursodeoxycholic acid.

Ursofalk 250mg/5ml suspension should be taken in accordance with the dosage regimen given above. The oral suspension must be taken regularly.

The use of Ursofalk 250mg/5ml suspension in primary biliary cirrhosis may be continued indefinitely.

In patients with primary biliary cirrhosis, in rare cases the clinical symptoms may worsen at the beginning of treatment, e.g. the itching may increase. Should this occur, therapy should first be continued with a reduced daily dose of Ursofalk suspension, and the dose then gradually increased (increase of the daily dose weekly) until the dose indicated in the respective dosage regimen is reached again.

Dissolution of Gallstones:

Adults: 8-12mg ursodeoxycholic acid (UDCA) per kg per day in two divided doses. The following dosage regime is recommended:

If doses are unequal the larger dose should be taken in late evening to counteract the rise in biliary cholesterol saturation which occurs in the early morning. The late evening dose may usefully be taken with food to help maintain bile flow overnight.

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 Ursofalk 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.

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

Children: Cholesterol rich gallstones are rare in children but when they occur, dosage should be related to bodyweight.

Ursofalk 250mg/5ml Suspension 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 cystic duct)

- frequent episodes of biliary colic

- radio-opaque calcified gallstones

- impaired contractility of the gall bladder

- hypersensitivity to bile acids or any excipient of the formulation

Ursofalk 250mg/5ml suspension 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 advance 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, Ursofalk suspension should not be used.

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

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

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

One measuring spoonful (5 ml) Ursofalk suspension contains 0.50 mmol (11.39mg) sodium. To be taken into consideration by patients on a controlled sodium diet.

Ursofalk 250mg/5ml suspension 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 Ursofalk 250mg/5ml suspension.

Ursofalk suspension 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.

In isolated cases, Ursofalk suspension can reduce the absorption of ciprofloxacin.

Ursodeoxycholic acid has been shown to reduce the plasma peak concentrations (C_max) and area under the curve (AUC) of the calcium antagonist nitrendipine. 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. Controlled clinical trials have shown, however, that ursodeoxycholic acid does not have a relevant inductive effect on cytochrome P450 3A enzymes.

Oestrogenic hormones and blood cholesterol lowering agents such as clofibrate may increase biliary lithiasis, which is a counter-effect to ursodeoxycholic acid used for dissolution of gallstones.

There are no adequate data from 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). Ursofalk suspension 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 Ursofalk 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.

It is not known whether ursodeoxycholic acid passes into breast milk. Therefore, Ursofalk suspension should not be taken during lactation. If treatment with Ursofalk suspension is necessary, the infant should be weaned.

No effects on the ability to drive and use machines have been observed.

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.

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.

UDCA is a bile acid which effects a reduction in cholesterol in biliary fluid primarily by dispersing the cholesterol and forming a liquid-crystal phase. UDCA affects the enterohepatic circulation of bile salts by reducing the ileal reabsorption of endogenous more hydrophobic and potentially toxic salts such as cholic and chenodeoxycholic acids.

In-vitro studies show that UDCA has a direct hepatoprotective effect and reduces the hepatotoxicity of hydrophobic bile salts. Immunological effects have also been demonstrated with a reduction in abnormal expression of HLS Class I antigens on hepatocytes as well as suppression of cytokine and interleukin production.

Ursodeoxycholic acid occurs naturally in the body. When given orally it is rapidly and completely absorbed. It is 96-98% bound to plasma proteins and efficiently extracted by the liver and excreted in the bile as glycine and taurine conjugates. In the intestine some of the conjugates are deconjugated and reabsorbed. The conjugates may also be dehydroxylated to lithocholic acid, part of which is absorbed, sulphated by the liver and excreted via the biliary tract.

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 2000mg of ursodeoxycholic acid per kg of body weight. In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mgper kg of body weight). Ursodeoxycholic acid had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.

Ursofalk 250mg/5ml Suspension contains the following excipients:

Benzoic acid (E210), microcrystalline cellulose and carboxymethyl-cellulose sodium, sodium chloride, sodium citrate, citric acid anhydrous, glycerol, propylene glycol, xylitol, sodium cyclamate, lemon flavouring (Givaudan 87017) and purified water.

None known other than the interactions identified in Section 4.5.

48 months.

Do not refrigerate or freeze.

Amber glass bottle closed with a plastic screw cap, containing 250ml of suspension.

Shake well before use. After opening the bottle, do not use after 4 months.

Dr Falk Pharma UK Ltd

Unit K, Bourne End Business Park

Cores End Road, Bourne End

Buckinghamshire, SL8 5AS

PL 10341/0007

31 December 2004

September 2011