Ursofalk

Ursodeoxycholic acid.

Capsule: 1 hard capsule of Ursofalk 250mg contains 250 mg ursodeoxycholic acid (UDCA) as the active substance.
FC tablet: One Ursofalk 500mg film-coated tablet contains 500 mg of ursodeoxycholic acid as the active substance.
Excipients/Inactive Ingredients: Capsule: Gelatin, Colloidal anhydrous silica, Magnesium stearate, Maize starch, Sodium dodecyl sulphate, Titanium dioxide (E 171), Purified water.
FC tablet: Magnesium stearate (Ph. Eur.), Polysorbate 80, Povidone K25, Microcrystalline cellulose, Colloidal anhydrous silica, Crospovidone (type A), Talc, Hypromellose, Macrogol 6000.

Pharmacotherapeutic group: Bile acid preparations. ATC code: A05AA02.
Pharmacology: Pharmacodynamics: Small amounts of ursodeoxycholic acid are found in human bile.
After oral administration, it reduces cholesterol saturation of the bile by inhibiting cholesterol absorption in the intestine and decreasing cholesterol secretion into the bile. Presumably as a result of dispersion of the cholesterol and formation of liquid crystals, a gradual dissolution of cholesterol gallstones occurs.
According to current knowledge, the effect of ursodeoxycholic acid in hepatic and cholestatic diseases is thought to be due to a relative exchange of lipophilic, detergent-like, toxic bile acids for the hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, to an improvement in the secretory capacity of the hepatocytes, and to immune-regulatory processes.
Pharmacokinetics: Orally administered ursodeoxycholic acid is rapidly absorbed in the jejunum and upper ileum through passive transport and in the terminal ileum through active transport. The rate of absorption is generally 60-80%. After absorption, the bile acid undergoes almost complete hepatic conjugation with the amino acids glycine and taurine and is then excreted with the bile. First-pass clearance through the liver is up to 60%.
Depending on the daily dose and underlying disorder or condition of the liver, the more hydrophilic ursodeoxycholic acid accumulates in the bile. At the same time, a relative decrease in other, more lipophilic, bile acids is observed.
Under the influence of intestinal bacteria, there is partial degradation to 7-keto-lithocholic acid and lithocholic acid. Lithocholic acid is hepatotoxic and causes liver parenchyma damage in a number of animal species. In humans, only very small amounts are absorbed, which are sulphated in the liver and thus detoxified, before being excreted in the bile and ultimately in the faeces.
The biological half-life of ursodeoxycholic acid is 3.5-5.8 days.
Toxicology: Preclinical safety data: 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 aplasia 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-/postnatal development of the offspring.

For the dissolution of cholesterol gallstones in the gall bladder. The gallstones must not show as shadows on X-ray images and should not exceed 15 mm in diameter. Gall bladder function must not be significantly impaired, despite the gallstones.
For the symptomatic treatment of primary biliary cirrhosis (PBC), provided there is no decompensated hepatic cirrhosis.
Capsule: For the treatment of bile reflux gastritis.

Capsule: The following daily dose is recommended for the various indications: For dissolution of cholesterol gallstones: (See Table 1.)

Click on icon to see table/diagram/image

The hard capsules should be swallowed whole with some liquid in the evening at bedtime.
They must be taken regularly.
The time required for the dissolution of gallstones is generally 6-24 months. If there is no reduction in the size of the gallstones after 12 months, the therapy should not be continued.
The success of the treatment should be checked by means of ultrasound or X-ray examination every 6 months. At the follow-up examinations, a check should be made to see whether calcification of the stones has occurred in the meantime. Should this be the case, the treatment must be ended.
For the treatment of bile reflux gastritis: 1 hard capsule of Ursofalk 250mg capsules should be swallowed whole with some liquid once daily in the evening before bedtime.
For the treatment of bile reflux gastritis Ursofalk 250mg capsules should normally be taken for 10 - 14 days. In general the duration of use depends on the course of the disease. The treating physician will decide on the duration of use in the individual case.
For the symptomatic treatment of primary biliary cirrhosis (PBC): The daily dose depends on body weight, and ranges from 3 to 7 hard capsules (14 ± 2 mg ursodeoxycholic acid per kg of body weight).
For the first 3 months of treatment, Ursofalk 250mg capsules should be taken in divided doses throughout the day. When the liver function parameters improve, the daily dose may be taken once daily in the evening. (See Table 2.)

Click on icon to see table/diagram/image

The hard capsules should be swallowed whole with some liquid. Ursofalk 250mg capsules must be taken regularly.
The use of Ursofalk 250mg capsules in PBC may be continued indefinitely.
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 event, therapy should first be continued with one Ursofalk 250mg capsules daily, and the dose then gradually increased (weekly increase of the daily dose by one hard capsule) until the dose indicated in the respective dosage regimen is reached again.
FC tablet: For patients weighing less than 47 kg or patients who are unable to swallow Ursofalk 500mg film-coated tablets, Ursofalk capsules or suspension are available.
The following daily dose is recommended for the various indications: For dissolution of cholesterol gallstones: (See Table 3.)

Click on icon to see table/diagram/image

The film-coated tablets should be swallowed whole with some liquid in the evening at bedtime. They must be taken regularly.
The time required for the dissolution of gallstones is generally 6-24 months. If there is no reduction in the size of the gallstones after 12 months, the therapy should not be continued. The success of the treatment should be checked by means of ultrasound or X-ray examination every 6 months. At the follow-up examinations, a check should be made to see whether calcification of the stones has occurred in the meantime. Should this be the case, the treatment must be ended.
For the symptomatic treatment of primary biliary cirrhosis (PBC): The daily dose depends on body weight and ranges from 1½ to 3½ film-coated tablets (14 ± 2 mg of ursodeoxycholic acid per kg of body weight).
For the first 3 months of treatment, Ursofalk 500mg film-coated tablets should be taken divided over the day. When the liver function parameters improve, the daily dose may be taken once daily in the evening. (See Table 4.)

Click on icon to see table/diagram/image

The film-coated tablets should be swallowed whole with some liquid. They must be taken regularly.
The use of Ursofalk 500mg film-coated tablets 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. In this event, therapy should first be continued with half an Ursofalk 500mg film-coated tablet or one Ursofalk capsule (containing 250 mg of ursodeoxycholic acid) daily, and the dose then gradually increased (weekly increase of the daily dose by half a film-coated tablet or one Ursofalk capsule) until the dose indicated in the respective dosage regimen is reached again. In this case the dose of Ursofalk should be reduced to one Ursofalk 250mg capsule daily and then gradually increased again until the dose indicated in the respective dosage regimen is reached again.

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.

Ursofalk 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; Radio-opaque calcified gallstones; Impaired contractility of the gall bladder; Hypersensitivity to bile acids or any excipient of the formulation.

Ursofalk 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/or nonresponders 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, Ursofalk should not be used.
When used for treatment of the advanced stages of primary biliary cirrhosis: In very rare cases decompensation of the 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.
Effects on ability to drive and use machines: No or negligible influence on ability to drive and use machines.
Capsule: Female patients taking Ursofalk 250mg capsules for dissolution of gallstones should use an effective non-hormonal method of contraception, since hormonal contraceptives may increase biliary lithiasis (see Interactions and Use in Pregnancy & Lactation).
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 Ursofalk 250mg capsules should be reduced to one Ursofalk 250mg capsule daily and then gradually increased again as described in Dosage & Administration.

Animal studies did not show an influence of ursodeoxycholic acid on fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions). Human data on fertility effects following treatment with ursodeoxycholic acid are not available.
There are no or limited amounts of data from the use of ursodeoxycholic acid in pregnant women. Studies in animals have shown reproductive toxicity during the early phase of gestation (see Pharmacology: Toxicology: Preclinical safety data under Actions). Ursofalk must not be used during pregnancy unless clearly necessary. 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 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.
According to few documented cases of breastfeeding women milk levels of ursodeoxycholic acid are very low and probably no adverse reactions are to be expected in breastfed infants.

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 the available data).
Gastrointestinal disorders: In clinical trials, reports of soft stools (capsule)/pasty stools (FC tablet) 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 tissue disorders: Very rarely, urticaria can occur.

Ursofalk 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 capsules/500 mg film-coated tablets.
Ursofalk 250mg capsules/500 mg film-coated tablets 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, Ursofalk 250mg capsules/500 mg film-coated tablets can reduce the absorption of ciprofloxacin.
Ursodeoxycholic acid has been shown to reduce plasma peak concentrations (C_max) 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 of the dose of nitrendipine may be necessary. An interaction with a reduction of the therapeutic effects 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.
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.
FC tablet: Female patients taking Ursofalk for dissolution of gallstones should use an effective non‐hormonal method of contraception, since hormonal contraceptives may increase biliary lithiasis.
Controlled clinical studies have shown, however, that ursodeoxycholic acid does not have a relevant inductive effect on cytochrome P450 3A enzymes.

Incompatibilities: None known to date.
Special precautions for disposal: No special requirements.

Shelf life: Capsule: 5 years.
FC tablet: 4 years.
Capsule: Store below 25°C.
FC tablet: Do not store above 25°C.

Cholagogues, Cholelitholytics & Hepatic Protectors

A05AA02 - ursodeoxycholic acid ; Belongs to the class of bile acids. Used in bile therapy.

POM