Lactulose

(BAN, USAN, rINN)
Lactulose Chemical formula
Synonyms: Lactulosa; Lactulosum; Laktulioze˙; Laktuloosi; Laktulos; Laktulosa; Laktüloz; Laktulóz. 4O
Cyrillic synonym: Лактулоза.

💊 Chemical information

Chemical formula: C12H22O11 = 342.3.
CAS — 4618-18-2.
ATC — A06AD11.
ATC Vet — QA06AD11.

Pharmacopoeias.

In Eur. and Jpn. Chin. only contains specifications for a solution. US only contains specifications for a solution and a concentrated liquid.

Ph. Eur. 6.2 (Lactulose). A white or almost white, crystalline powder. Freely soluble in water; sparingly soluble in methyl alcohol; practically insoluble in toluene.

Ph. Eur. 6.2 (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.

USP 31

(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. Hypernatraemia has been reported.

Lactic acidosis.

Severe lactic acidosis developed in a patient with adynamic ileus who was being given lactulose for hepatic encephalopathy.1
1. Mann NS, et al. Lactulose and severe lactic acidosis. Ann Intern Med 1985; 103: 637.

💊 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.

💊 Pharmacokinetics

Taken orally, lactulose passes essentially unchanged into the large intestine where it is metabolised by saccharolytic 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 about 3.35 g of lactulose per 5 mL, 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 mL) given daily in a single dose or in 2 divided doses; doses up to 45 mL 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.
1. Clausen MR, Mortensen PB. Lactulose, disaccharides and colonic flora: clinical consequences. Drugs 1997; 53: 930–42
2. Schumann C. Medical, nutritional and technological properties of lactulose: an update. Eur J Nutr 2002; 41 (suppl): I17–I25.

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.1 The lack of a standardised test solution has hampered comparison of test results. Although hyperosmolar solutions are better at determining intestinal damage,2 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.3 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.4 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.5
1. Uil JJ, et al. Clinical implications of the sugar absorption test: intestinal permeability test to assess mucosal barrier function. Scand J Gastroenterol 1997; 223 (suppl): 70–8
2. Uil JJ, et al. Sensitivity of a hyperosmolar or ″low″-osmolar test solution for sugar absorption in recognizing small intestinal mucosal damage in coeliac disease. Dig Liver Dis 2000; 32: 195–200
3. Di Leo V, et al. Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea. Am J Gastroenterol 2003; 98: 2245–52
4. Miller MA, et al. Comparison of scintigraphy and lactulose breath hydrogen test for assessment of orocecal transit: lactulose accelerates small bowel transit. Dig Dis Sci 1997; 42: 10–18
5. Pimentel M, et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci 2003; 48: 86–92.

💊 Preparations

BP 2008: Lactulose Oral Powder; Ph. Eur.: Liquid Lactulose; USP 31: Lactulose Solution.

Proprietary Preparations

Arg.: Genocolan; Lactulon; Lafelax; Medixin; Tenualax; Austral.: Actilax; Duphalac; Genlac; Lac-Dol; Lactocur; Austria: Bifiteral; Duphalac; Laevolac; Belg.: Bifiteral; Certalac†; Duphalac; Braz.: Colonac; Farlac; Lactulona; Pentalac†; Canad.: Acilac†; Gen-Lac; Laxilose†; Chile: Axant; Dismam; Duphalac; Rencef†; Cz.: Duphalac; Lactecon; Laevolac†; Denm.: Danilax†; Medilax; Fin.: Duphalac; Levolac; Loraga†; Fr.: Duphalac; Laxaron; Ger.: Bifinorma; Bifiteral; Eugalac; Hepa-Merz Lact†; Hepaticum-Lac-Medice†; Kattwilact†; Lactocur; Lactuflor; Lactuverlan; Laevilac S; Medilet†; Tulotract; Gr.: Duphalac; Purgolac†; Hong Kong: Danilax; Duphalac; Laevolac; Martulose; Hung.: Duphalac; Laevolac; India: Duphalac; Livoluk; Indon.: Constipen; Dulcolactol; Duphalac; Lactulax; Lantulos; Laxadilac; Opilax; Pralax; Solac; Irl.: Dulax; Duphalac; Gerelax; Laxose; Israel: Avilac; Gerelax; Lactulax; Laevolac; Ital.: Biolac†; Dia-Colon; Duphalac; Epalat EPS; Epalfen; Lactoger†; Laevolac; Lassifar†; Lattubio†; Lattulac; Lis†; Normase; Osmolac†; Sintolatt; Verelait; Jpn: Monilac; Malaysia: Dhactulose; Duphalac; Lactul; Lactumed†; Mex.: Lactulax; Regulact; Neth.: Duphalac; Epalfen; Laxeersiroop; Legendal; Norw.: Duphalac; Levolac; NZ: Laevolac; Philipp.: Duphalac; Lilac; Pol.: Duphalac; Lactulol; Normalac; Normase; Port.: Colsanac; Duphalac; Lactecon†; Laevolac; Obstipar; Rus.: Duphalac (Дюфалак); Normase (Нормазе); Portalac (Порталак); S.Afr.: Adco-Liquilax; Duphalac; Lacson; Laxette; Singapore: Dhactulose; Duphalac; Lactus; Spain: Belmalax; Duphalac; Swed.: Duphalac; Laktipex; Loraga; Switz.: Duphalac; Gatinar; Legendal; Rudolac; Thai.: Duphalac; Hepalac; Laevolac†; Turk.: Duphalac; Lactulac; Laevolac; Laktol; Osmolak; UAE: Soflax; UK: Duphalac; Lactugal; Lemlax; Regulose; USA: Cephulac; Cholac†; Chronulac; Constilac; Constulose; Duphalac; Enulose; Kristalose; Venez.: Lactulona; Moderan. Multi-ingredient: Arg.: Bifidosa; Fr.: Melaxose; Transulose; Ger.: Eugalan To p f e r ; Indon.: Laktobion; Ital.: Combilax; Lactolas; Lactomannan; Levoplus; Naturalass; Neth.: Transulose; Port.: Melaxose.
Published January 23, 2019.