Lactulose is a synthetic disaccharide in solution form for oral or rectal administration. Each 15 mL of Lactulose Solution USP contains 10 g lactulose (and less than 1.6 g galactose, less than 1.2 g lactose, and 0.1 g or less of fructose). It also contains D&C Yellow No. 10, FD & C Yellow No. 6 and Purified Water.

Lactulose is a colonic acidifier for treatment and prevention of portal-systemic encephalopathy.

The chemical name for lactulose is 4-O-β-D-galactopyranosyl-D-fructofuranose. It has the following structural formula:

The molecular weight is 342.30. It is freely soluble in water.

For the prevention and treatment of portal-systemic encephalopathy, including the stages of hepatic pre-coma and coma.

Controlled studies have shown that lactulose solution therapy reduces the blood ammonia levels by 25 to 50%; this is generally paralleled by an improvement in the patients' mental state and by an improvement in EEG patterns. The clinical response has been observed in about 75% of patients, which is at least as satisfactory as that resulting from neomycin therapy. An increase in patients' protein tolerance is also frequently observed with lactulose therapy. In the treatment of chronic portal-systemic encephalopathy, lactulose has been given for over 2 years in controlled studies.

Oral

Adult: The usual adult, oral dosage is 2 to 3 tablespoonfuls (30 to 45 mL, containing 20 g to 30 g of lactulose) three or four times daily. The dosage may be adjusted every day or two to produce 2 or 3 soft stools daily.

Hourly doses of 30 to 45 mL of lactulose solution 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 dose of lactulose may then be reduced to the recommended daily dose. Improvement in the patient's condition may occur within 24 hours but may not begin before 48 hours or even later.

Continuous long-term therapy is indicated to lessen the severity and prevent the recurrence of portal-systemic encephalopathy. The dose of lactulose for this purpose is the same as the recommended daily dose.

Pediatric: Very little information on the use of lactulose in young children and adolescents has been recorded. As with adults, the subjective goal in proper treatment is to produce 2 or 3 soft stools daily. On the basis of information available, the recommended initial daily oral dose in infants is 2.5 to 10 mL in divided doses. For older children and adolescents, the total daily dose is 40 to 90 mL. If the initial dose causes diarrhea, the dose should be reduced immediately. If diarrhea persists, lactulose should be discontinued.

Rectal

When the adult patient is in the impending coma or coma stage of portal- systemic encephalopathy and the danger of aspiration exists, or when the necessary endoscopic or intubation procedures physically interfere with the administration of the recommended oral doses, lactulose solution may be given as a retention enema via a rectal balloon catheter. Cleansing enemas containing soap suds or other alkaline agents should not be used.

Three hundred mL of lactulose solution should be mixed with 700 mL of water or physiologic saline and retained for 30 to 60 minutes. Lactulose enema may be repeated every 4 to 6 hours. If this lactulose enema is inadvertently evacuated too promptly, it may be repeated immediately.

The goal of treatment is reversal of the coma stage in order that the patient may be able to take oral medication. Reversal of coma may take place within 2 hours of the first enema in some patients. Lactulose given orally in the recommended doses, should be started before lactulose by enema is stopped entirely.

Lactulose Solution USP (Oral or Rectal Solution), 10 g/15 mL, is a clear, yellow to golden-yellow solution supplied in one pint (473 mL) and two quart (1.89 L) bottles. Lactulose solution contains: 667 mg lactulose/mL (10 g/15 mL).

Store at 25° C (77° F); excursions permitted to 15-30°C (59-86°F) (see USP Controlled Room Temperature). Do not freeze. Keep tightly closed.

Under recommended storage conditions, a normal darkening of color may occur. Such darkening is characteristic of sugar solutions and does not affect therapeutic action.

Prolonged exposure to temperatures above 86° F (30° C) or to direct light may cause extreme darkening and turbidity which may be pharmaceutically objectionable. If this condition develops, do not use. Prolonged exposure to freezing temperatures may cause change to a semisolid, too viscous to pour. Viscosity will return to normal upon warming to room temperature.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.

Manufactured by: Novex Pharma, Richmond Hill, Ontario Canada L4C 5H2. Manufactured for: Apotex Corp. Weston, FL 33326. July 2003. FDA rev date: 7/28/2003

Precise frequency data are not available.

Lactulose may produce gaseous distention with flatulence or belching and abdominal discomfort such as cramping in about 20% of patients. Excessive dosage can lead to diarrhea with potential complications such as loss of fluids, hypokalemia, and hypernatremia. Nausea and vomiting have been reported.

There have been conflicting reports about the concomitant use of neomycin and lactulose solution. 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. Thus the status of the lactulose-treated patient should be closely monitored in the event of concomitant oral anti-infective therapy.

Results of preliminary studies in humans and rats suggest that nonabsorbable antacids given concurrently with lactulose may inhibit the desired lactulose-induced drop in colonic pH. Therefore, a possible lack of desired effect of treatment should be taken into consideration before such drugs are given concomitantly with lactulose.

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 lactulose dosage has been achieved.

A theoretical hazard may exist for patients being treated with lactulose solution who may be required to undergo electrocautery procedures during proctoscopy or colonoscopy. Accumulation of H₂ 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 a non-fermentable solution. Insufflation of CO₂ as an additional safeguard may be pursued but is considered to be a redundant measure.

General: Since lactulose solution contains galactose (less than 1.6 g/15 mL) and lactose (less than 1.2 g/15 mL), it should be used with caution in diabetics.

In the overall management of portal-systemic encephalopathy, it should be recognized that there is serious underlying liver disease with complications such as electrolyte disturbance (e.g., hypokalemia) for which other specific therapy may be required.

Infants receiving lactulose may develop hyponatremia and dehydration.

Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility.

There are no known animal data on long-term potential for mutagenicity.

Administration of lactulose solution in the diet of mice for 18 months in concentrations of 3 and 10 percent (v/w) did not produce any evidence of carcinogenicity.

In studies in mice, rats, and rabbits, doses of lactulose solution up to 6 or 12 mL/kg/day produced no deleterious effects on breeding, conception, or parturition.

Pregnancy: Teratogenic Effects; Pregnancy Category B. Reproduction studies have been performed in mice, rats, and rabbits at doses up to 2 or 4 times the usual human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to lactulose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lactulose solution is administered to a nursing woman. Pediatric Use: Very little information on the use of lactulose in pediatric patients has been recorded (see DOSAGE AND ADMINISTRATION).

Signs and Symptoms: There have been no reports of accidental overdosage. In the event of overdosage, it is expected that diarrhea and abdominal cramps would be the major symptoms. Medication should be terminated.

Oral LD₅₀: The acute oral LD50 of the drug is 48.8 mL/kg in mice and greater than 30 mL/kg in rats.

Dialysis: Dialysis data are not available for lactulose. It's molecular similarity to sucrose, however, would suggest that it should be dialyzable.

Since lactulose solution contains galactose (less than 1.6 g/15 mL), it is contraindicated in patients who require a low galactose diet.

Lactulose causes a decrease in blood ammonia concentration and reduces the degree of portal-systemic encephalopathy. These actions are considered to be results of the following:

Bacterial degradation of lactulose in the colon acidifies the colonic contents.

This acidification of colonic contents results in the retention of ammonia in the colon as the ammonium ion. Since the colonic contents are then more acid than the blood, ammonia can be expected to migrate from the blood into the colon to form the ammonium ion.

The acid colonic contents convert NH₃ to the ammonium ion (NH₄)+, trapping it and preventing its absorption.

The laxative action of the metabolites of lactulose then expels the trapped ammonium ion from the colon.

Experimental data indicate that lactulose is poorly absorbed. Lactulose given orally to man and experimental animals resulted in only small amounts reaching the blood. Urinary excretion has been determined to be 3% or less and is essentially complete within 24 hours.

When incubated with extracts of human small intestinal mucosa, lactulose was not hydrolyzed during a 24-hour period and did not inhibit the activity of these extracts on lactose. Lactulose reaches the colon essentially unchanged. There it is metabolized by bacteria with the formation of low molecular weight acids that acidify the colon contents.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

LACTULOSE - ORAL

(LACK-tew-lohss)

COMMON BRAND NAME(S): Chronulac, Constilac, Constulose, Duphalac, Evalose, Kristalose

USES: This medication is a laxative used to treat constipation. It may help to increase the number of bowel movements per day and the number of days you have a bowel movement. Lactulose is a colonic acidifier that works by increasing stool water content and softening the stool. It is a man-made sugar solution.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug, but may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if has been so prescribed by your health care professional.

This drug is also used to treat or prevent complications of liver disease (hepatic encephalopathy).

HOW TO USE: Take this medication by mouth, usually once daily for constipation, or as directed by your doctor. If you are taking the solution, to improve the taste, you may mix it into fruit juice, water, milk, or a soft dessert. If you are using the crystals in packets, dissolve the contents of the packet in half a glass of water (4 ounces or 120 milliliters), or as directed by your doctor.

Use this medication regularly in order to get the most benefit from it. Remember to take it at the same time each day. Dosage is based on your medical condition and response to therapy.

It may take up to 48 hours to have a bowel movement. Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Gas, bloating, burping, stomach rumbling/pain, nausea, and cramps may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: diarrhea, vomiting, muscle cramps/weakness, irregular heartbeat, mental/mood changes, seizures.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking lactulose, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a low galactose diet (e.g., a diet that includes few or no milk products), certain other bowel problem (bowel obstruction).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes.

The elderly may be at a greater risk for loss of blood minerals (e.g., potassium, sodium) while using this drug, especially if they are using it for an extended time.

Do not take any other laxative medications while taking this drug. Frequent use or overuse of laxatives can cause a severe loss of body water (dehydration). This is especially likely to occur in children or the elderly. Contact your doctor immediately if you develop any of the following symptoms of dehydration: muscle weakness, muscle cramps, dizziness.

Before having surgery or other procedures (e.g., electrocautery), tell your doctor or surgeon that you are using this medication.

This medication contains different sugars. If you have diabetes, this medication may affect your blood glucose levels. Monitor your blood glucose regularly, and share the results with your doctor. Your anti-diabetic medications or diet may need to be adjusted.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: antacids containing aluminum and/or magnesium, other laxatives.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe stomach cramps, diarrhea.

NOTES: Do not share this product with others.

If you use this product for an extended time, laboratory and/or medical tests (e.g., blood mineral levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not freeze because this will make the medication too thick to pour. If it becomes frozen, warm it to room temperature until it is pourable again. A normal darkening of color may occur. If too much darkening occurs and you cannot swallow it, discard the medication and get a refill. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.