INFORMATION FOR HEALTH PROFESSIONALS
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ALPHA-LACTULOSE is a clear, colourless to slightly yellow, aqueous syrup with a specific gravity of 1.33. Each 15mL contains lactulose 10g, galactose <1.65g, lactose <0.9g and traces of other sugars.
Lactulose is a synthetic disaccharide used in the treatment of constipation and in hepatic encephalopathy.
Studies in patients with a history of chronic constipation have shown that lactulose therapy causes a significant increase in the number of bowel movements per day and the number of days on which bowel movements occur.
Lactulose reaches the colon virtually unchanged. There it is metabolised by colonic bacteria to lactic acid and other shortchain carboxylic acids. The end result is a change in the osmotic pressure and acidification of the colonic contents resulting in an increase in stool water content with resultant distention and softening of the stool which in turn promotes increased peristalsis and bowel evacuation. It may take 48 hours before an effect is obtained.
Hepatic encephalopathy (Portal -systemic encephalopathy, hepatic coma) is a neuropsychiatric syndrome which can complicate all forms of hepatic disease. It is generally accepted that it involves exposure of the brain to nitrogenous substances arising from the gut from bacterial metabolism of protein, with ammonia being implicated most commonly together with an alteration of the pattern of amino acids entering the central nervous system. The basic action of lactulose in hepatic encephalopathy is aimed at reducing nitrogenous intoxication by decreasing blood ammonia concentration. Lactulose is degraded in the large bowel by bacterial flora mainly to acetic and lactic acids thus reducing the intraluminal pH to below 5. This acidification of colonic contents results in the retention of ammonia as the ammonium ion. Ammonia, amines and various amides, and other basic nitrogenous substances are thus trapped reducing their absorption into the blood. Since the colonic contents are more acidic than the blood ammonia can be expected to migrate from the blood into the colon to form ammonium ion. Lowering of faecal pH is also thought to suppress urase producing organisms and to foster the growth of saccharolytic bacteria rather than E. coli, a more efficient ammonia producing bacterium. The diarrhoeal action of lactulose is synergistic in repelling the trapped ammonium ion from the colon.
The therapeutic action of lactulose in ameliorating the symptoms of hepatic encephalopathy is considered to be a result of the following:
The actual mechanism may be a combination of these effects.
In the treatment of chronic portal-systemic encephalopathy studies have shown that lactulose syrup reduces the blood ammonia levels by 25-50% and this is generally paralleled by an improvement in the patient's mental state and by an improvement in EEG patterns. The clinical response has been observed in 75% of patients which is at least as satisfactory as that resulting from neomycin therapy, with the added benefit that an increase in the patient's protein tolerance is frequently observed with lactulose therapy. Lactulose is an effective alternative to neomycin particularly in patients with hearing problems or renal disease or when long-term use is anticipated.
Experimental data on lactulose given orally to humans indicates that lactulose is poorly absorbed from the gastrointestinal tract and no enzymes capable of hydrolysis of lactulose into its component monosaccharides are known to be present in human gastrointestinal tissue. Lactulose reaches the colon virtually unchanged 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.
Lactulose given orally to humans results in only small amounts reaching the blood by absorption through the small intestine probably by a nonmediated diffusion mechanism. The small increases in blood sugar are probably attributable to the small amounts of galactose and lactose also present in lactulose syrup. The small amount of absorbed lactulose is subsequently excreted unchanged in the urine (3% or less) within 24 hours. A small quantity of lactulose is probably hydrolysed in the colon into its constituent monosaccharides, galactose and fructose. The end result is a change in osmotic pressure and acidification of the colonic contents resulting in an increase in stool water content with resultant distension and softening of the stool which in turn promotes increased peristalsis and bowel evacuation.
Administration of lactulose to infants fed with cows' milk produces a predominance of lactobacilli in the stools thus simulating the intestinal flora following maternal milk feeding. Lactulose also appears to increase the production of lysosome in infants receiving cows' milk.
For adults the usual dosage for the management of Portal-systemic encephalopathy is 30-45mL three to four times daily. The dosage may be adjusted every day or two to produce two or three soft stools daily.
Hourly doses of 30-45mL may be used to induce the rapid laxation indicated in the initial phase of the therapy of Portal-systemic encephalopathy. When the laxative effect has been achieved the dosage may be reduced to the recommended daily dose. Improvement in the patient's condition may take 24 hours to occur. Continuous long term therapy is indicated to lessen the severity and prevent the occurrence of Portal-systemic encephalopathy. The dosage for this purpose is the same as the recommended daily dose.
For chronic constipation the dosage is individualised and may depend upon the severity of the constipation. The dosage range is 10-45mL given in a single daily dose preferably after breakfast. The usual initial adult dose is 15-30mL daily. Since lactulose syrup relieves constipation by producing a physiological change in the colon it may take 48 hours before normal defecation occurs. After three days the dose may be reduced to 10-20mL for maintenance.
For children a dose of 10-20mL is recommended. The usual initial dose is 3-5mL for infants less than 1 year of age; 5-10mL for children aged 1-5 years and 15mL for children 6-12 years of age.
A theoretical hazard may exist for patients treated with lactulose syrup who may be required to undergo electrocautery procedures during proctoscopy or colonoscopy if sugars reach the colon then bacterial breakdown causes hydrogen production. Accumulation of hydrogen gas in significant concentration in the presence of an electrical spark may result in an explosive reaction. Although this complication has not been reported with lactulose, patients on lactulose therapy undergoing such procedures should have a thorough bowel cleansing with nonfermentable solution.
Lactulose syrup contains galactose and lactose and should be used with caution in diabetics as blood glucose levels may be elevated, usually after extended use.
Chronic misuse of laxatives may result in electrolyte imbalance, in particular serum potassium levels may be decreased. Elderly debilitated patients who receive lactulose syrup for more than 6 months should have serum electrolytes measured periodically.
In the overall management of portal-systemic encephalopathy it should be recognised that there is a per-existing hepatic disease and efforts should be made to identify and treat the precipitating cause of hepatic coma. The overall management should include dietary protein restriction, bowel cleansing and sterilisation, correction of electrolyte and fluid imbalance, provision of caloric and nutritional needs and treatment of underlying hepatic disease. Other laxatives should not be used especially during the initial phase of therapy for portal-systemic encephalopathy because the loose stools resulting from their use may falsely suggest that adequate dosing has been achieved
Reproduction studies with daily oral doses of lactulose syrup up to 12mL/kg in mice and rats and 6mL/kg in rabbits have not revealed any evidence of an increased occurrence of foetal damage or other deleterious effects.
Lactulose syrup has been shown to be safe and effective for the treatment of constipation associated with pregnancy when administered to women at different stages of pregnancy. Its use during pregnancy should be on the advice of a medical practitioner.
There is no data on the secretion of lactulose in breastmilk or the effect on the breastfed infant. It should not be given to breastfeeding women unless the benefits to the mother outweigh the potential risks to the feeding infant.
It is recommended that if lactulose syrup is given to infants or children for periods greater than one month that this should be done under medical supervision.
Lactulose may cause abdominal discomfort associated with flatulence or cramps in about 20% of patients. These effects are usually mild and transient.
Nausea and vomiting have occasionally been reported following high doses. Anorexia and increased thirst have also been reported.
Prolonged use or excessive dosage may result in diarrhoea with excessive loss of water and electrolytes, particularly potassium.
Hypernatraemia has been reported.
Neomycin: There have been conflicting reports about the concomitant use of neomycin and lactulose syrup although in some situations the two medicines administered together are more effective than either one alone.
Theoretically the elimination of certain colonic bacteria by neomycin and possibly other anti-infective agents may interfere with the desired degradation of lactulose and thus prevent the acidification of colonic contents. There have been some reports that lactulose fermenting bacteria are relatively resistant to neomycin which may explain why a combination could work in some cases. The status of the lactulose treated patient should be closely monitored in the event of concomitant oral antibiotic therapy.
No toxicity in humans has been recorded to date. There have been no reports of accidental overdosage. In the event of acute overdosage it is expected that diarrhoea and abdominal cramps would be the major symptoms.
Store below 25°C. Protect from light.
General Sale Medicine
Bottles contain 500mL
Epilactose, fructose and tagalose are also present in small quantities.
ALPHA PHARMACEUTICALS LTD,
Melville House
159 Broadway Avenue
PO Box 705
Palmerston North
Tel: 06) 355-1066
Fax: (06) 356-6293
21 July 1999