Ursodeoxycholic Acid 150 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ursodeoxycholic Acid 150 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 150 mg of ursodeoxycholic acid.
Also contains 142.50 mg of lactose monohydrate.
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White to off-white, round tablet, 11 mm diameter with a break line. The tablets are marked with ‘URS 150’.
The break line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
The dissolution of radiolucent (i.e. non-radio opaque) cholesterol gallstones in patients with a functioning gallbladder.
4.2 Posology and method of administration
Adults and the elderly
Dissolution of gallstones:
A daily dose of 8 to 12mg/kg ursodeoxycholic acid will produce cholesterol desaturation in the majority of cases. The measurement of the lithogenic index on bile-rich duodenal drainage fluid after 4-6 weeks of therapy may be useful for determining the minimum effective dose. The lowest effective dose has been found to be 4 mg/kg. The daily dose for most patients is 3 or 4 tablets, according to body weight. The dose should be divided into two administrations after meals, with one administration always after the evening meal.
The duration of treatment needed to achieve dissolution will not usually exceed 2 years, and should be monitored with regular cholecystograms. Treatment should be continued for 3-4 months after the radiological disappearance of gallstones.
Any temporary discontinuation of treatment, if prolonged for 3-4 weeks, will allow the bile to return to a state of supersaturation, and will extend the total time taken for litholysis. In some cases stones may recur after successful treatment.
Children and adolescents
Not recommended
For oral administration.
4.3 Contraindications
• Acute inflammation of the gallbladder 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 gallbladder.
• Non functioning gall bladder.
• Hypersensitivity to bile acids or to any of the excipients in the formulation
• 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
4.4 Special warnings and precautions for use
During the first 3 months of treatment, the liver function parameters AST (SGOT), ALT (SGPT) and y-GT should be monitored by the physician every 4 weeks, thereafter every 3 months.
When used for the 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 gallbladder 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.
The active ingredient ursodeoxycholic acid is used for the treatment of primary biliary cirrhosis. Ursodeoxycholic Acid 150 mg Tablets is not indicated for the use in the treatment of this condition.
If the gallbladder cannot be visualised on X-ray images, or in cases of calcified gallstones, impaired contractility of the gallbladder or frequent episodes of biliary colic, Ursodeoxycholic Acid should not be used.
If diarrhoea occurs, the dose must be reduced and in cases of persistent diarrhoea, the therapy should be discontinued.
Excessive dietary intake of calories and cholesterol should be avoided; a low cholesterol diet will probably improve the effectiveness of Ursodeoxycholic Acid tablets.
Ursodeoxycholic Acid tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Bile acid binding resins (e.g., colestyramine, colestipol) and some antacids (e.g. aluminium hydroxide) may inhibit the absorption and efficacy of Ursodeoxycholic Acid. 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 may reduce Ursodeoxycholic Acid absorption.
Ursodeoxycholic acid can increase the absorption of ciclosporin and raises ciclosporin serum levels which 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.
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.
It is recommended that drugs known to increase cholesterol elimination in bile, such as oestrogenic hormones, oral contraceptive agents and certain blood cholesterol lowering agents, should not be prescribed concomitantly.
4.6 Fertility, 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). Ursodeoxycholic Acid must not be used during pregnancy unless clearly necessary.
Women of child bearing age should use adequate non-hormonal or low oestrogen oral contraceptive measures during treatment with ursodeoxycholic acid. However, in patients taking Ursodeoxycholic Acid for dissolution of gallstones, effective nonhormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis. The possibility of a pregnancy must be excluded before beginning treatment.
There are no clinical data available on the safety of ursodeoxycholic acid in women who are breast-feeding. Therefore, Ursodeoxycholic Acid is not recommended in this patient group.
4.7 Effects on ability to drive and use machines
No effects on the ability to drive and use machines have been observed.
4.8 Undesirable effects
No significant alterations have so far been observed in liver function.
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).
|
System Organ Class |
Frequency |
Adverse Event |
|
Gastrointestinal disorders |
Common |
Diarrhoea, pasty stools |
|
Not known |
Vomiting, nausea | |
|
Hepatobiliary disorders |
Very rare |
Calcification of gallstones |
|
Skin and subcutaneous disorders |
Very rare |
Urticaria |
|
Not known |
Pruritus |
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 national reporting system (see below):
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
Pharmacovigilence Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.img.ie
E-mail: imbpharmacovigilance@imb.ie
4.9 Overdose
Diarrhoea may occur. 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Bile Acid Preparations ATC Code: A05AA02
Ursodeoxycholic acid is a gallstone dissolving agent which acts by reducing the content of cholesterol in bile. This may be due either to a reduction in hepatic cholesterol synthesis or reduced absorption of cholesterol or both
5.2 Pharmacokinetic properties
Intestinal absorption after an oral dose of ursodeoxycholic acid is high, with a first-pass clearance of about 50 to 60%. Studies show that passive diffusion occurs, whereupon the drug enters the enterohepatic circulation and is subject to an efficient hepatic extraction mechanism. The 'spillover' into the systemic blood supply is therefore minimal. Plasma levels are not clinically important but may be useful in estimating patient compliance; they reach maximum concentrations at about 60 minutes after ingestion with another peak recorded at 3 hours.
Ursodeoxycholic acid is rapidly conjugated with glycine and taurine in the liver. Microbial biotransformation of the drug and its metabolites occurs when they leave the enterohepatic circulation and is responsible for high levels of faecal lithocholic and 7-ketolithocholic acids during ursodeoxycholic acid therapy. Intestinal flora also hydrolyse conjugated drug back to the parent compound and interconvert ursodeoxycholic and chenodeoxycholic acids.
5.3 Preclinical safety data
Ursodeoxycholic acid has not shown teratogenic potential in rats and rabbits; embryotoxicity seen in the rat at high doses appears to occur early in gestation.
Bile acids act as tumour promoters in colon carcinogenesis, but there is no evidence that they are direct carcinogens. In two year carcinogenicity studies ursodeoxycholic acid was not tumourigenic in mice. In rats an increase in adrenal phaeochromocytomas was observed which is not considered to be clinically significant.
Ursodeoxycholic acid has low oral toxicity. However, at high doses, the liver has been shown to be a target organ in all animal species examined (due to the hepatotoxic nature of the metabolite, lithocholic acid). These effects were seen at doses 3-80 fold higher on a body weight basis than the maximum daily dose proposed for humans.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Pregelatinised maize starch Sodium starch glycolate Talc
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
None.
6.5 Nature and contents of container
PVC/Aluminium blisters.
60 tablets packaged into a cardboard carton.
6.6 Special precautions for disposal
None.
7 MARKETING AUTHORISATION HOLDER
Auden Mckenzie (Pharma Division) Ltd
McKenzie House
Bury Street
Ruislip
Middlesex
HA47TL
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 17507/0228
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28/05/2014
10 DATE OF REVISION OF THE TEXT
28/05/2014