Lactulose

Pronunciation

Class: Ammonia Detoxicants
VA Class: AD400
CAS Number: 4618-18-2
Brands: Cholac, Chronulac, Constilac, Constulose, Enulose, Generlac, Kristalose

Introduction

A synthetic derivative of lactose; an ammonia detoxicant and laxative.1 2

Uses for Lactulose

Portal-Systemic Encephalopathy

Used as an adjunct to protein restriction and supportive therapy for prevention and treatment of portal-systemic encephalopathy (PSE), including hepatic pre-coma and coma.1

Useful in the management of PSE resulting from surgical portacaval shunts or chronic hepatic diseases such as cirrhosis.1

Reduces blood ammonia concentration, which usually leads to substantial improvement in patient’s mental state and EEG tracings.1

Does not alter the course of underlying liver disease and therefore does not obviate treatment of such disease or PSE.1

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Since neomycin destroys bacteria and lactulose requires bacterial degradation for its effectiveness, concomitant therapy with these agents is theoretically counterproductive.1 (See Anti-infective Agents under Interactions.) However, some evidence suggests that concomitant therapy with lactulose and neomycin may be more effective than either drug alone.1

Not useful in the management of non-nitrogenous types of encephalopathy such as those induced by drugs or metabolic or electrolyte disturbances.1 Not effective in the treatment of coma associated with infectious hepatitis or other acute liver disorders.1

Chronic Constipation

Useful as a laxative in the treatment of chronic constipation in adults,2 including geriatric patients.1 Superiority compared with conventional laxatives not established.1

Used in the treatment of chronic constipation in children; safety and efficacy in children not established.1

Used to restore regular bowel movements following hemorrhoidectomy.1

Used to induce bowel evacuation in geriatric patients with colonic retention of barium and severe constipation following barium meal examination.1

Lactulose Dosage and Administration

Administration

Administer orally, via gastric tube, or rectally.1 2

Oral Administration

When solution is administered orally, may minimize sweet taste by diluting with water, fruit juice, milk or by adding to food (e.g., desserts).1

When administering via gastric tube, dilute well to prevent induction of vomiting and possible aspiration pneumonia.1

Reconstitution

For oral administration, reconstitute powder by dissolving contents of a 10- or 20-g packet in approximately 120 mL of water.1

Rectal Administration

May administer rectally to adults with PSE during stages of hepatic pre-coma or coma when the possibility of aspiration exists or when necessary endoscopic or intubation procedures interfere with oral administration.1

Reconstitution

For rectal administration, dilute 200 g of powder in 700 mL of water or 0.9% sodium chloride solution and administer via a rectal balloon catheter.1

Dosage

Each 15 mL of commercially available lactulose solution provides approximately 10 g of the drug; corresponding doses provided by 2.5, 5, 7.5, 10, 30, 40, 45, 90, 150, and 300 mL of the commercial solution are approximately 1.67, 3.3, 5, 6.67, 20, 27, 30, 60, 100, and 200 g, respectively.1 Following reconstitution of the oral powder as directed, a 10- or 20-g dose is provided by administering the total volume.1

Pediatric Patients

Portal-Systemic Encephalopathy
Oral

Infants (limited data): Initially, 1.67–6.67 g daily in divided doses.1

Older children and adolescents: Initially, 27–60 g daily recommended by manufacturer.1

Adjust dosage every 1–2 days as necessary to produce 2–3 soft stools daily.1

If the initial dose produces diarrhea, reduce dose immediately; if diarrhea persists, discontinue drug.1

Chronic Constipation

At least 5 g daily, usually given as a single dose after breakfast, has been used.1

Adults

Portal-Systemic Encephalopathy
Oral

20–30 g 3 or 4 times daily.1

Adjust dosage every 1–2 days as necessary to produce 2 or 3 soft stools daily.1 Usually dosage is 60–100 g daily; some patients may require higher dosage.1

Some clinicians recommend dosage adjustment according to acidity of colonic contents by measuring stool pH (with indicator paper) at initiation of therapy and adjusting dosage until stool pH is about 5.1 This pH is usually achieved when the patient has 2 or 3 soft stools daily during therapy.1

In the management of acute PSE episodes, give 20–30 g orally at 1- to 2-hour intervals to induce rapid laxation.1 When the laxative effect has been achieved, reduce dosage to the amount required to produce 2 or 3 soft stools daily.1

During treatment, improvement in patient’s clinical condition usually occurs within 1–3 days.1

Continuous long-term therapy with lactulose may decrease severity and prevent recurrence of PSE.1

Rectal

For reversal of hepatic coma, 200 g is diluted with 700 mL of water or 0.9% sodium chloride solution and administered rectally via a rectal balloon catheter; solution is retained for 30–60 minutes.1

Retention enemas may be administered every 4–6 hours.1 If enema retained for <30 minutes, may repeat administration immediately.1

In some patients, reversal of hepatic coma may occur within 2 hours of the first enema.1 Before discontinuance of lactulose retention enemas, initiate recommended oral dosages of the drug.1

Chronic Constipation
Oral

Usual initial dosage is 10–20 g daily.1 2 Dosage may be increased to 40 g daily if necessary.1

Following oral administration, 24–48 hours may be required to restore normal bowel movements.1

To facilitate bowel movements in patients undergoing hemorrhoidectomy, administer 10 g twice daily on the day before surgery and twice daily for 5 days postoperatively.1

To induce bowel evacuation in geriatric patients with colonic retention of barium and severe constipation following barium meal examination, 3.3–6.7 g twice daily for 1–4 weeks has been administered.1

Special Populations

Hepatic Impairment

Hepatic Impairment
Oral

No specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

Renal Impairment
Oral

No specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

No specific dosage recommendations for geriatric patients.1

Cautions for Lactulose

Contraindications

  • Patients who require a low-galactose diet.1 2

Warnings/Precautions

Warnings

Patients Who May Require Electrocautery Procedures

Administer with caution to patients who may require electrocautery procedures during proctoscopy or colonoscopy; the drug can cause accumulation of hydrogen gas in high concentrations, which in the presence of an electrical spark may theoretically result in an explosive reaction.1 Although such events have not been reported to date, patients receiving lactulose therapy should have a thorough bowel cleansing with a nonfermentable solution prior to these procedures.1 Insufflation of carbon dioxide may be used but probably is unnecessary.1

General Precautions

Electrolyte Disturbances

In the treatment of PSE, important to consider that serious underlying liver disease may produce complications such as electrolyte disturbances (e.g., hypokalemia) that require additional therapy.1 In addition, if diarrhea occurs, it may severely deplete fluids and potassium and may intensify symptoms of PSE.1 For these reasons, some clinicians recommend periodic determinations of serum potassium concentrations during long-term treatment with lactulose.1

Diabetes Mellitus

Since lactulose solution contains some free lactose and galactose, the drug should be used with caution in patients with diabetes mellitus.1

Specific Populations

Pregnancy

Category B.2

Lactation

Not known if lactulose is distributed into milk.1 Use with caution in nursing women.1 2

Pediatric Use

Safety and efficacy for the treatment of chronic constipation in children not established.1 2

Geriatric Use

Determine serum electrolyte concentrations (e.g., potassium, chloride, carbon dioxide) periodically during therapy in geriatric, debilitated patients who receive lactulose for >6 months.1

Common Adverse Effects

Gaseous distention,1 belching,1 flatulence,1 2 borborygmi,1 abdominal discomfort (e.g., cramping).1 2 Dehydration and hyponatremia in infants.1

Interactions for Lactulose

Laxatives

Do not administer laxatives concomitantly; resultant loose stools may be falsely interpreted as an indication that adequate dosage of lactulose has been achieved.1

Anti-infective Agents

Theoretical concern that concomitantly administered oral neomycin and possibly other anti-infective agents could eliminate colonic bacteria necessary to metabolize lactulose and thereby prevent acidification of the colon contents.1 However, lactulose appears to remain active when administered with neomycin to patients with PSE, and some reports suggest that such concomitant therapy may be more effective than either drug alone in the treatment of PSE.1

Patients receiving lactulose and an oral anti-infective agent should be closely monitored for possible inadequate response to lactulose.1

Antacids

Limited data suggest that nonabsorbable antacids administered concomitantly with lactulose may inhibit the desired decrease in fecal pH in the colon.1

The potential lack of desired effect of lactulose should be considered before concomitant use of a nonabsorbable antacid.1

Lactulose Pharmacokinetics

Absorption

Extent

Poorly absorbed from GI tract.1 2

Onset

Does not exert its effect until it reaches the colon.2

Extent

Less than 3% absorbed from small intestine following oral administration; negligible absorption from colon.1

Elimination

Metabolism

Absorbed drug not metabolized.1 Unabsorbed drug reaches colon unchanged, where it is metabolized by bacteria to form lactic acid and small amounts of acetic and formic acids.1

Elimination Route

Absorbed drug excreted in urine unchanged within 24 hours.1

Stability

Storage

Oral

Powder and Solution

15–30°C (powder and solution); avoid freezing of solution.1 Prolonged exposure to freezing temperatures may result in solution that is semisolid and too viscous to pour; viscosity returns to normal following warming to room temperature.1

Although heat causes cloudiness and heat and light cause darkening of the solution, these changes do not indicate loss of potency.1

Actions and Spectrum

  • A disaccharide containing one molecule each of galactose and fructose.1

  • Causes a decrease in blood ammonia concentration in patients with PSE and reduces the degree of PSE.1

  • Mechanism of action not clearly defined.1

  • Breakdown of lactulose to organic acids (i.e., lactic acid and small amounts of formic and acetic acids) by the saccharolytic bacteria in the colon acidifies colon contents.1

  • Acidification of colon contents inhibits the nonionic diffusion of ammonia from the colon into the blood.1 Since colon contents are more acidic than is blood, ammonia can diffuse from the blood into the colon.1

  • In the acidic colon, ammonia (NH3) is converted to ammonium ions (NH4+) thereby preventing its absorption.1 In a similar manner, the absorption of amines (which may also contribute to the development of PSE) also may be reduced.1

  • Finally, the cathartic action of lactulose (probably caused by the osmotic effect of its organic acid metabolites) expels the trapped ammonium ions and possibly other nitrogenous substances from the colon.1

  • The osmotic effect of the organic acid metabolites of lactulose causes an increase in water content of the stool and a softening of the stool; this effect on the stool may not be seen until 24–48 hours after administration of the drug.1

  • In patients with chronic constipation, the drug increases the number of bowel movements per day and the number of days when bowel movements occur.1

Advice to Patients

  • Importance of not using cleansing enemas containing soapsuds or other alkaline agents concomitantly.1

  • Importance of contacting clinician if an unusual diarrheal condition occurs during therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Lactulose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

For solution

10 g/packet

Kristalose (with <0.3 g of galactose and lactose total)

Bertek, (also promoted by Cumberland)

20 g/packet

Kristalose (with <0.3 g of galactose and lactose total)

Bertek, (also promoted by Cumberland)

Solution

3.33 g/5 mL*

Chronulac Syrup (with <733 mg of galactose, <400 mg of lactose, and ≤400 mg of other sugars)

Aventis

Constilac Syrup (with <733 mg of galactose, <400 mg of lactose, and ≤400 mg of other sugars)

Alra

Constulose (with <733 mg of galactose, <400 mg of lactose, and ≤400 mg of other sugars)

Alpharma

Oral or Rectal

Solution

3.33 g/5 mL*

Cholac Syrup (with <733 mg of galactose, <400 mg of lactose, and ≤400 mg of other sugars)

Alra

Enulose (with <733 mg of galactose, <400 mg of lactose, and ≤400 mg of other sugars)

Alpharma

Generlac (with <733 mg of galactose, <400 mg of lactose, and ≤400 mg of other sugars)

Morton Grove

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Kristalose 10GM Packet (CUMBERLAND PHARMACEUTICALS): 30/$55.99 or 90/$149.97

Kristalose 20GM Packet (CUMBERLAND PHARMACEUTICALS): 30/$86.25 or 90/$240.95

Lactulose Encephalopathy 10GM/15ML Solution (HI-TECH): 473/$19.98 or 1419/$59.94

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. AHFS Drug Information 2003. McEvoy, GK, ed. Lactualose.Bethesda, MD: American Society of Health-System Pharmacists; 2003:2479-81.

2. Bertek. Kristalose (lactulose) for oral solution prescribing information. In: Physicians’ desk reference. 58th ed. Montvale, NJ: Medical Economics Company Inc; 2004:962-3.

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