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Lactulose

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Synonyms: Lactulosa; Lactulosum; Laktulóz; Laktuliozė; Laktuloosi; Laktulos; Laktulosa
BAN: Lactulose
USAN: Lactulose
INN: Lactulose [rINN (en)]
INN: Lactulosa [rINN (es)]
INN: Lactulose [rINN (fr)]
INN: Lactulosum [rINN (la)]
INN: Лактулоза [rINN (ru)]
Chemical name: 4-O-β-d-Galactopyranosyl-d-fructose
Molecular formula: C12H22O11 =342.3
CAS: 4618-18-2
ATC code: A06AD11

Pharmacopoeias. In Europe and Japan. China only contains specifications for a solution. US only contains specifications for a solution and a concentrated liquid.

European Pharmacopoeia, 6th ed. (Lactulose). A white or almost white, crystalline powder. Freely soluble in water sparingly soluble in methyl alcohol practically insoluble in toluene.

European Pharmacopoeia, 6th ed. (Lactulose, Liquid; Lactulose Solution BP 2008). An aqueous solution of lactulose. It contains not less than 62.0% w/v of lactulose it may contain lesser amounts of other sugars including lactose, epilactose, galactose, tagatose, and fructose. It may contain a suitable antimicrobial preservative. It is a clear, colourless or pale brownish-yellow, viscous liquid. Miscible with water. It may be a supersaturated solution or may contain crystals that disappear on heating.

The United States Pharmacopeia 31, 2008 (Lactulose Concentrate). A colourless to amber syrupy liquid that may exhibit some precipitation and darkening on standing. Miscible with water. Store in airtight containers preferably at a temperature between 2° and 30°.

Adverse Effects

Lactulose may cause abdominal discomfort associated with flatulence or cramps. Nausea and vomiting have occasionally been reported after high doses. Some consider the taste to be unpleasant this can be minimised by dilution in water, fruit juice, or milk, or by mixing the dose with food. Prolonged use or excessive dosage may result in diarrhoea with excessive loss of water and electrolytes, particularly potassium. Hypernatrae-mia has been reported.

Lactic acidosis. Severe lactic acidosis developed in a patient with adynamic ileus who was being given lactulose for hepatic encephalopathy.

Precautions

Lactulose should not be given to patients with galactosaemia or intestinal obstruction. It should not be used in patients on a low galactose diet and care should be taken in patients with lactose intolerance or in diabetic patients because of the presence of some free galactose and lactose.

 

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Pharmacokinetics

Taken orally, lactulose passes essentially unchanged into the large intestine where it is metabolised by sac-charolytic bacteria with the formation of simple organic acids, mainly lactic acid and small amounts of acetic and formic acids. The small amount of absorbed lactulose is subsequently excreted unchanged in the urine.

Uses and Administration

Lactulose is a synthetic disaccharide osmotic laxative used in the treatment of constipation and in hepatic encephalopathy. Lactulose is broken down by colonic bacteria mainly into lactic acid. This exerts a local osmotic effect in the colon resulting in increased faecal bulk and stimulation of peristalsis. It may take up to 48 hours before an effect is obtained. When larger doses are given for hepatic encephalopathy the pH in the colon is reduced significantly and the absorption of ammonium ions and other toxic nitrogenous compounds is decreased, leading to a fall in blood-ammonia concentration and an improvement in mental function.

Lactulose is usually given orally as a solution containing about3.35 g of lactulose per 5 niL, with other sugars such as galactose and lactose an oral powder formulation is also available in some countries. In the treatment of constipation, the usual initial dose is 10 to 20 g (15 to 30 rriL) given daily in a single dose or in 2 divided doses doses up to 45 niL daily of the solution (or up to 40 g of the reconstituted oral powder formulation) have been given. The dose is gradually adjusted according to the patient’s needs. For doses in children, see below.

In hepatic encephalopathy, an oral dose of 60 to 100 g (90 to 150 mL) is given daily in 3 divided doses. The dose is subsequently adjusted to produce 2 or 3 soft stools each day. Lactulose solution 200 g (300 mL) mixed with 700 mL of water or sodium chloride 0.9% has been used as a retention enema the enema is retained for 30 to 60 minutes, repeated every 4 to 6 hours until the patient is able to take oral medication.

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Administration in children. In the UK, children may be given the following oral doses of lactulose 3.35 g per 5 mL solution for constipation doses may be adjusted according to response:

• 1 month to 1 year: 2.5 mL twice daily

• 1 to 5 years: 5 mL twice daily

• 5 to 10 years: 10 mL twice daily

• 10 to 18 years: 15 mL twice daily

Diagnosis and testing, the sugar absorption test. In healthy individuals lactulose is largely unabsorbed from the gastrointestinal tract, but in, for example, coeliac disease there is increased permeability to disaccharides such as lactulose and a paradoxical decrease in the absorption of monosaccharides. This led to the development of the differential sugar absorption test in which 2 sugars are given simultaneously by mouth and the urinary recovery of each is determined mannitol is commonly used as the monosaccharide component and lactulose as the disaccharide. Alternatives include mannitol plus cellobiose and rhamnose plus lactulose. This absorption test is useful in the investigation of intestinal disease.

The lack of a standardised test solution has hampered comparison of test results. Although hyperosmolar solutions are better at determining intestinal damage, some have preferred to use low osmolar solutions because of the risk of inducing osmotic diarrhoea, especially in children.

A study found the sugar absorption test to be strongly predictive of an organic cause of chronic diarrhoea it may be useful in improving the selection of patients who need further evaluation.

THE LACTOSE BREATH TEST (hydrogen breath test). Lactulose is converted by bacteria in the large bowel to short chain fatty acids with the production of small quantities of hydrogen gas. The hydrogen is rapidly absorbed and is exhaled in the breath and measurement of its production is used to measure orocaecal transit time and carbohydrate malabsorption. However, even small doses of lactulose shortens transit time, which may limit the value of this test.

The test is also diagnostic for bacterial overgrowth in the small intestine, which is increased in irritable bowel syndrome. Although hydrogen is produced in most subjects, methane is also produced in up to 50% of healthy subjects, and data suggest there may be clinical implications to different gas profiles. A study found that the presence of methane was associated with constipation, and with constipation-predominant irritable bowel syndrome. Methane production was infrequent in diarrhoea-predominant irritable bowel syndrome and virtually absent in inflammatory bowel disease. Diarrhoea and inflammatory bowel disease were associated with hydrogen production. Whether the type of bacterial flora causally determines symptoms is as yet unknown.

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Preparations

British Pharmacopoeia 2008: Lactulose Oral Powder

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1and 6.2: Liquid Lactulose The United States Pharmacopeia 31, 2008: Lactulose Solution.

Proprietary Preparations

 

Argentina: Genocolan Lactulon Lafelax Medixin Tenualax

Australia:: Actilax Duphalac Genlac Lac-Dol Lactocur

Austria: Bifiteral Duphalac Laevolac

Belgium: Bifiteral Certalacf Duphalac

Brazil: Colonac Farlac Lactulona Pen-talacf

Canada: Acilacf Gen-Lac Laxilosel

Chile: Axant Dismam Duphalac Rencef †

Czech Republic: Duphalac Lactecon Laevolac †

Denmark: Danilaxl Medilax

Finland: Duphalac Levolac Loraga †

France: Duphalac Laxaron

Germany: Biflnorma Bifiteral Eugalac Hepa-Merz Lact † Hepaticum-Lac-Medice † Kattwilact † Lactocur Lactuflor Lactuverlan Laevilac S Medilet † Tulotract

Greece: Duphalac Purgolac †

Hong Kong: Danilax Duphalac Laevolac Martulose

Hungary: Duphalac Laevolac

India: Duphalac Livoluk

Indonesia: Constipen Dulcolactol Duphalac Lactulax Lantulos Laxadilac Opilax Pralax Solac

Ireland: Dulax Duphalac Gerelax Laxose

Israel: Avilac Gerelax Lactulax Laevolac

Italy: Biolac † Dia-Colon Duphalac Epalat EPS Epalfen Lac-toger † Laevolac Lassifar † Lattubio-L Lattulac Lis-P Normase Osmolacl Sintolatt Verelait

Japan: Monilac

Malaysia: Dhactulose Duphalac Lactul Lactumed †

Mexico: Lactulax Regulact

The Netherlands: Duphalac Epalfen Laxeer-siroop Legendal

Norway: Duphalac Levolac

New Zealand: Laevolac

Philippines: Duphalac Lilac

Poland: Duphalac Lactulol Normalac Normase

Portugal: Colsanac Duphalac Lactecon † Laevolac Obstipar

Russia: Duphalac Normase Portalac

South Africa: Adco-Liquilax Duphalac Lacson Laxette

Singapore: Dhactulose Duphalac Lactus

Spain: Belmalax Duphalac

Sweden: Duphalac Laktipex Loraga

Switzerland: Duphalac Gatinar Legendal Rudolac

Thailand: Duphalac Hepalac Laevolac †

Turkey: Duphalac Lactulac Laevolac Laktol Osmolak

United Arab Emirates: Soflax

UK: Duphalac Lactugal Lemlax Regulose

USA: Cephulac Cholac † Chronulac Constilac Constulose Duphalac Enulose Kristalose

Venezuela: Lactulona Noderan

Multi-ingredient

Argentina: Bifidosa

France: Nelaxose Transulose

Germany: Eugalan Topfer

Indonesia: Laktobion

Italy: Combilax Lactolas Lactomannan Levo-plus Naturalass

The Netherlands: Transulose

Portugal: Nelaxose

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