SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT Lactulose-MIP 650 mg/ml oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml of oral solution contains 650 mg of lactulose.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM Oral solution. Clear colourless or yellowish, viscous liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications  Constipation, which cannot be influenced sufficiently by high-roughage diet or other general measures, as well as diseases requiring easy defecation.  Prevention and treatment of portal systemic encephalopathy.

4.2 Posology and method of administration Posology Lactulose is taken orally. The dosage recommendations given below are meant as guidelines only, and hence are to be adapted to the requirements of the individual patients according to the severity and development of their condition. The quantities indicated can be measured with the accompanying measuring cup.

Constipation: Adults and adolescents (14-17 years): The initial dose is 15-30 ml daily, taken either in a single dose (preferably in the morning) or in two divided doses. When the bowel movement begins, the dose should be reduced by half. If no response is seen in 3 days, the dosage may be raised to twice the initial dose. If still no response is observed a doctor should be consulted. If the patient has been treated with laxatives for a greater period of time, these should be discharged gradually.

Children, daily dosage: Under 1 year: 5 ml 1-6 years: 10-15 ml 7-14 years 15 ml

The dosage should be individually adjusted, producing bowel movements with soft stool.

Portal systemic encephalopathy (PSE) Acute PSE (precoma and coma hepaticum): Initially 50 ml every 2 hours until 2 bowel movements producing stools. Thereafter the dose should be adjusted to a dose that produces 2-3 soft stools daily. Chronic PSE: Initially 30-45 ml 3 or 4 times a day, thereafter the dose should be adjusted to produce 2-3 soft stools daily.

1 Method of administration Lactulose-MIP may be taken diluted in water or other liquids. It can be taken any time regardless of meals. The laxative effect may occur within 2 to 10 hours. If the dose is inadequate, the first stool may occur within 24 to 48 hours. The duration of the treatment depends on the development of the clinical picture of the patient.

4.3 Contraindications Bowel obstruction. Galactose intolerance. Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use Lactulose-MIP should not be used in case of acute inflammatory gastrointestinal diseases and disturbances of water and electrolyte balance.

Use in special patient groups Lactulose-MIP should not be used in patients with hereditary fructose intolerance, lactase deficiency or glucose-galactose malabsorption because the medicinal product contains fructose, galactose and lactose due to the manufacturing process.

Especially in new-born infants, infants and toddlers autosomal recessive hereditary fructose intolerance should be excluded. In these patients the incomplete degradation may lead to fructosemia and fructosuria, hypoglycaemia and hypoglycaemic hepatic, renal and cerebral damages.

Information for diabetics and patients with other disturbances of carbohydrate metabolism This medicinal product contains in 1 measuring cup, corresponding to 30 ml solution, a maximum content of 7.8 g of digestible carbohydrates, e.g. fructose, galactose, lactose, equivalent to 0.65 bread units. For this reason caution should be exercised in case of diabetics, when using the maximum dosage in treatment of portal systemic encephalopathy.

4.5 Interaction with other medicinal products and other forms of interaction Lactulose can increase the loss of potassium induced by other active substances (e.g. diuretics, corticosteroids and amphotericin B). The concomitant application of cardiac glycosides may result in an enhancement of the effect of the glycosides because of potassium deficiency.

4.6 Fertility, pregnancy and lactation To date, no harmful effects of lactulose on the embryo/foetus in humans have been reported, however, no relevant epidemiological data are available. In animal studies lactulose did not show teratogenic effects (see section 5.3). Because of the pharmacological and pharmacokinetic properties of lactulose, harmful effects on the unborn or nursed child are not to be expected at the present state of knowledge. Therefore Lactulose-MIP can be used during pregnancy and lactation if administered as prescribed.

4.7 Effects on ability to drive and use machines Lactulose-MIP has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects Gastrointestinal disorders Very common ( 1/10): Mild abdominal pain, meteorism, flatulence at the beginning of the treatment. Common (1/100 to <1/10): Nausea, vomiting, diarrhoea at higher dosage levels.

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Metabolism and nutrition disorders Rare (1/10,000 to <1/1,000): Hypernatraemia in the therapy of portal systemic encephalopathy. The usual disturbances in water and electrolyte balance associated with laxatives and their sequelae have to be taken into account if dosages regularly producing thin stools are administered over a prolonged period of time.

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 listed in Appendix V.

4.9 Overdose Symptoms of intoxication: In overdosage nausea, vomiting, diarrhoea and loss of electrolytes may occur.

Therapy of intoxication: Symptomatic balancing measures.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Osmotically acting laxatives ATC-Code: A06AD11

Lactulose, a disaccharide consisting of galactose and fructose, cannot be hydrolysed by the disaccharidases of the small intestine.

In the colon lactulose is degraded by bacterial enzymes to low molecular organic acids, in particular lactic acid and acetic acid, as well as to methane and hydrogen.

Two mechanisms are responsible for the laxative effect of lactulose:

 The sugar and acids induce an osmotic retention of water resulting in an increased volume of the colon content and an indirect stimulation of intestinal peristalsis.  The stimulation of the intestinal peristalsis has been attributed to direct action of the acids.

As to the effect of decreasing ammonia, different mechanisms are discussed:

 The degradation of lactulose causes a pH decrease resulting in a protonation of ammonia. Thus, absorbable and toxic ammonia is converted into non-absorbable and non-toxic ammonium ions. Therefore, the absorption of ammonia from the colon is reduced.  Due to the excess of carbohydrates and the resulting pH decrease the proteolytic intestinal flora is reduced in favour of the saccharolytic intestinal flora and therefore, fewer ammonia is produced.  The decreased pH in the intestine causes ammonia to be passed directly from the blood into the acidic intestine content.  The administration of lactulose leads to an excess of carbohydrates in the colon resulting in a relative deficit in nitrogen for the bacterial flora which then is being compensated by microbial ammonia consumption.

In portal systemic encephalopathy lactulose achieves a 25 to 50 % reduction of blood ammonia levels and a therapeutic effect may be expected within a few hours to a few days.

3 5.2 Pharmacokinetic properties Only 0.4 to 2.0 % of orally applied lactulose are absorbed from the small intestine and eliminated unchanged by urinary excretion. Only part of the acids formed in the colon are absorbed and metabolised.

5.3 Preclinical safety data Preclinical data based on studies of single and repeated dose toxicity reveal no special hazards for humans. A long-term animal study does not give reference to tumorigenic potential. Lactulose was not teratogenic in mice, rats and rabbits. After oral administration, systemic toxicity of Lactulose-MIP is not to be expected due to the pharmacological and pharmacokinetic properties of lactulose.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Citric acid, anhydrous Cherry flavour Water, purified.

Lactulose-MIP also contains fructose, galactose and lactose due to the manufacturing process.

6.2 Incompatibilities Not applicable.

6.3 Shelf life 3 years. The shelf-life after first opening of the bottle is 6 months.

6.4 Special precautions for storage Do not store above 30°C.

6.5 Nature and contents of container The lactulose solution is filled into PET bottles. The screw cap consists of polyethylene. The measuring cup consists of polypropylene and has a graduation in a range of 5 – 30 ml.

Pack sizes

100 ml, 200 ml, 500 ml, 1000 ml Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements.

7. MARKETING AUTHORISATION HOLDER

(to be completed/adapted nationally)

4 8. MARKETING AUTHORISATION NUMBER(S)

(to be completed/adapted nationally)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

(to be completed/adapted nationally)

10. DATE OF REVISION OF THE TEXT

(to be completed/adapted nationally)

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