SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ursodeoxycholic Acid Glenmark 250 mg hard capsule

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250 mg of ursodeoxycholic acid.

Excipient with known effect:

Sunset Yellow (E110) 0.42 mg per hard capsule

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsules, hard.

Hard gelatin capsules with 2 tightly closed parts (cap and body) orange-opaque colour, size 0, about 21.4 mm containing white or almost white granular powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ursodeoxycholic acid is indicated:

•    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. The gall bladder must be functioning despite the gallstone(s).

•    For the treatment of primary biliary cirrhosis (PBC), provided there is no decompensated hepatic cirrhosis.

Paediatric population

• Hepatobiliar disorder associated with cystic fibrosis in children aged 6 years to less than 18 years

4.2 Posology and method of administration

Posology

The daily dose is determined by therapeutic indication.

Symptomatic treatment of the of _ primary biliary cirrhosis (PBC)

Stage I-III

The daily dose depends on body weight and ranges from 3 to 7 hard capsules of ursodeoxycholic acid 250 mg (12 - 16 mg of UDCA per kg of body weight per day).

For the first 3 months of treatment, ursodeoxycholic acid 250 mg should be taken divided over the day. With improvement of the liver values the daily dose may be taken once daily in the evening.

The recommended treatment schedule is as follows:

Body weight (kg)	Daily dose (mg/kg of body weight)
		Morning	Midday	Evening
47 - 62 kg	12-16	1	1	1
63 - 78 kg	13-16	1	1	2
79 - 93 kg	13-16	1	2	2
94 - 109 kg	14-16	2	2	2
Over 110 kg	7 hard capsules	2	2	3

Stage IV:

In combination with increased serum bilirubin levels (> 40 pg/L; conjugated), only half the normal dosage should initially be given (see dosage for stages I - III), (6 - 8 mg ursodeoxycholic acid per kg body weight per day, equivalent to about 2 to 3 Ursodeoxycholic acid 250 mg hard capsules).

Thereafter, liver function should be closely monitored for several weeks (once every 2

weeks for 6 weeks). If there is no deterioration in liver function (AP, ALAT, ASAT,

gamma-GT, bilirubin) and if no increased pruritus occurs, the dosage can be increased

further to the usual level. However, liver function should again be closely monitored for several weeks. Once again, if there is no deterioration in liver function, the patient can be maintained at the normal dosage over the long term.

Patients with primary biliary cirrhosis (stage IV) without increased serum bilirubin levels are allowed to receive the normal starting dose immediately (see dosage stages I - III).

However, close monitoring of liver function, as described above, is likewise applicable in such cases; treatment of primary biliary cirrhosis will need to be regularly assessed on the basis of liver (laboratory) values and clinical findings

The use of ursodeoxycholic acid 250 mg hard 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 case the dose should be reduced to 250mg daily and then gradually increased (increased daily dose per week) until the indicated dose in the dosing schedule is again obtained.

For dissolution of cholesterol gallstones:

Adults: The usual dose is 8-12 mg ursodeoxycholic acid (UDCA) per kg body weight per day, taken in the evening before bedtime according to:

-    up to 60 kg: 2 capsules

-    61-80 kg: 3 capsules

-    81-100 kg: 4 capsules

-    above 100 kg: 5 capsules

Care should be taken to ensure that they are taken regularly.

The time required for dissolution of gallstones is generally 6-24 months, depending on stone size and composition.

The success of the treatment should be checked by means of ultrasound or X-ray examination every 6 months. Treatment should be continued until absence of calculi after 2 cholecystography and / or ultrasounds successive performed after 4-12 weeks, because these techniques do not allow visualization of smaller stones 2 mm.

Elderly

There is no evidence to suggest that any alteration in the adult dose is needed.

Paediatric population

Cholesterol rich gallstones and PBC:Cholesterol rich gallstones and PBC are very rare in children but when they occur, dosage should be related to bodyweight. There is no age limit for ursodeoxycholic acid administration, the active ingredient of Ursodeoxycholic Acid Glenmark. If the patient cannot swallow capsules or has a bodyweight below 47 kg, other pharmaceutical forms (suspension) are available.

Children with cystic fibrosis aged 6 years to less than 18 years: 20 mg/kg/day in 2-3 divided doses, with a further increase to 30 mg/kg/day if necessary

Method of administration

The hard capsules should be swallowed whole with a glass of water. For patients weighing less than 47 kg or patients who are unable to swallow Ursodeoxycholic Acid Glenmark, a suspension is available.

4.3 Contraindications

Ursodeoxycholic acid 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 to any of the excipients listed in section 6.1. Paediatric population

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

4.4 Special warnings and precautions for use

Ursodeoxycholic Acid Glenmark should be taken under medical supervision.

During the first 3 months of treatment, liver function parameters AST (SGOT), ALT (SGPT) and y-GT should be monitored by the physician every 4 weeks, thereafter every 3 months. Apart from allowing for identification of responders and nonresponders in patients being treated for PBC, this monitoring would also enable early detection of potential hepatic deterioration, particularly in patients with advanced stage PBC.

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.

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 visualized (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 visualized on X-ray images, or in cases of calcified gallstones, impaired contractility of the gall bladder or frequent episodes of biliary colic, ursodeoxycholic acid should not be used.

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.

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

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 one ursodeoxycholic acid 250 mg hard capsule daily and then gradually increased again as described in section 4.2.

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

Excipients

Ursodeoxycholic Acid Glenmark contain Sunset Yellow Aluminium Lake (E110) colouring agent which may cause allergic reactions.

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 UDCA 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 ursodeoxycholic acid.

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 UDCA (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.

UDCA has been shown to reduce peak plasma concentrations (Cmax) and area under the curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers.

Closed monitoring of the outcome of concurrent use of nitrendipine and UDCA is recommended. An increase of the dose of the 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 from the use of UDCA 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 breastfeeding women milk levels of Ursodeoxycholic acid are very low and probably no adverse reactions are to be expected in breastfed 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 list below provides information on the undesirable effects identified from clinical experience, categorised by incidence and System Organ Class body system.

Undesirable effects are ranked under headings of frequency using the following convention; very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Gastrointestinal disorders:

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

Very rarely, severe right upper abdominal pain has occurred during the treatment of PBC

Hepatobiliary disorders:

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

During therapy of the advanced stages of PBC, 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.

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 Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Diarrhoea may occur in cases of overdose. In general, other symptoms of overdose are unlikely because the absorption of UDCA 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 UDCA therapy (28-30 mg/kg/day) in patients with primary sclerosing cholangitis (off-label use) was associated with higher rates of serious adverse events.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: therapy gallbladder, bile acid preparations, ATC code: A05AA02

Small amounts of UDCA 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 UDCA 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 UDCA, to an improvement in the secretory capacity of the hepatocytes, and to immune-regulatory processes.

Paediatric population

Cystic fibrosis

From clinical reports long-term experience up to 10 years and more is available with UDCA treatment in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can decrease bile duct proliferation, halt progression of histological damage and even reverse hepato-biliary changes if given at early stage of CFAHD. Treatment with UDCA should be started as soon as the diagnosis of CFAHD is made in order to optimize treatment effectiveness.

5.2 Pharmacokinetic properties

Ursodeoxycholic acid administered orally is rapidly absorbed in the jejunum and upper iliac portion through passive transport and through active transport in the terminal iliac portion._About 90% of the administered dose is absorbed after oral administration of ursodeoxycholic acid. After absorption, the bile acid undergoes complete hepatic conjugation with amino acids glycine and taurine and then is excreted in gallbladder. Clearance first-pass metabolism is up to 60%. Depending on the daily dose and the underlying disease or the condition of the liver, the largest quantity of ursodeoxycholic acid is accumulated in the gallbladder. At the same time, it is observed a relative decrease of other bile acids more lipophilic.

Under the influence of intestinal bacteria, partial degradation occurs to 7-cetolitocolic and lithocholic acid. Lithocholic acid is hepatotoxic and produces destruction of liver parenchyma of a number of animal species.

In humans, only very small amounts are absorbed, which are sulfated in the liver and thus before being detoxified are excreted in the gallbladder and finally in the faeces.

The half-life of ursodeoxycholic acid is 3.5 to 5.8 days.

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 UDCA, 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 UDCA having carcinogenic potential.

In vitro and in vivo genetic toxicology tests with UDCA were negative. The tests with UDCA revealed no relevant evidence of a mutagenic effect.

d) Toxicity to reproduction

In studies in rats, tail aplasias 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). UDCA 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

Capsule content:

StarCap 1500 (maize starch, pregelatinized starch) Crosspovidone (E1202)

Sodium lauryl sulphate Colloidal silicon dioxide, anhydrous Magnesium stearate (E572)

Capsule shell:

Gelatine (E441)

Sunset Yellow (E110)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

DATE OF REVISION OF THE TEXT

26/10/2016