1. Name Of The Medicinal Product
Ursofalk 250mg hard capsules
2. Qualitative And Quantitative Composition
Each capsule of Ursofalk contains the following active ingredient:
ursodeoxycholic acid 250mg
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
White, opaque, hard gelatin capsules (size0) containing a white compressed powder or granules.
4. Clinical Particulars
4.1 Therapeutic Indications
Ursofalk is indicated in the treatment of primary biliary cirrhosis (PBC) and for the dissolution of radiolucent gallstones in patients with a functioning gall bladder
4.2 Posology And Method Of Administration
There are no age restrictions on the use of Ursofalk 250mg hard capsules. For patients weighing less than 47 kg or patients who are unable to swallow Ursofalk 250mg hard capsules, Ursofalk suspension is available.
The following daily dose is recommended for the various indications:
For primary biliary cirrhosis (PBC)
The daily dose depends on body weight, and ranges from 3 to 7 capsules (14 ± 2 mg ursodeoxycholic acid per kg of body weight).
For the first 3 months of treatment, Ursofalk 250mg hard capsules should be taken divided over the day. With improvement of the liver values the daily dose may be taken once daily in the evening.
|
|
| |||
| subsequently | ||||
|
|
|
| ||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The capsules should be swallowed whole with some liquid. Care should be taken to ensure that they are taken regularly.
The use of Ursofalk 250mg hard capsules 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 be continued with 1 capsule daily, and the therapy gradually increased (increase of the daily dose weekly by 1 capsule) 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.
4.3 Contraindications
Ursofalk 250mg hard capsules 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
4.4 Special Warnings And Precautions For Use
Ursofalk 250mg hard capsules 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, Ursofalk 250mg hard capsules 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Ursofalk 250mg hard capsules 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 hard capsules.
Ursofalk 250mg hard capsules 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 250mg hard capsules can reduce the absorption of ciprofloxacin.
Ursodeoxycholic acid has been shown to reduce the plasma peak concentrations (Cmax) and the 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 ursodeoxcholic acid does not have a relevant induction 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.
4.6 Pregnancy And Lactation
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). Ursofalk 250mg hard capsules 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 250mg hard capsules 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 250mg hard capsules should not be taken during lactation. If treatment with Ursofalk 250mg hard capsules is necessary, the infant should be weaned.
4.7 Effects On Ability To Drive And Use Machines
No effects on ability to drive and use machines have been observed.
4.8 Undesirable Effects
The evaluation of undesirable effects is based on the following frequency data:
Very common (
Common (
Uncommon (
Rare (
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.
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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
5.2 Pharmacokinetic Properties
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.
5.3 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 malformations occurred after a dose of 2000 mg 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 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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Ursofalk 250mg hard capsules contain the following excipients:
Maize starch, colloidal anhydrous silica, magnesium stearate, gelatin, titanium dioxide
6.2 Incompatibilities
None known.
6.3 Shelf Life
36 months.
6.4 Special Precautions For Storage
None
6.5 Nature And Contents Of Container
Clear PVC blister strips with aluminium foil backing packed in cardboard cartons. Available in cartons containing 60 capsules packaged in six blister strips of 10 capsules or 100 capsules packaged in 4 blister strips of 25 capsules.
6.6 Special Precautions For Disposal And Other Handling
None
7. Marketing Authorisation Holder
Dr Falk Pharma UK Ltd
Unit K
Bourne End Business Park
Cores End Road
Bourne End
Buckinghamshire
SL8 5AS
8. Marketing Authorisation Number(S)
PL 10341/0006
9. Date Of First Authorisation/Renewal Of The Authorisation
31 December 2004
10. Date Of Revision Of The Text
September 2011
No comments:
Post a Comment