Lactulose

INDICATIONS AND USAGE 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 the 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.

DOSAGE AND ADMINISTRATION Oral Adult: The usual adult, oral dosage is 2 to 3 tablespoonfuls (30 mL to 45 mL, containing 20 grams to 30 grams 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 mL 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 mL to 10 mL in divided doses. For older children and adolescents the total daily dose is 40 mL 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.

CONTRAINDICATIONS Since LACTULOSE For Oral Solution contains galactose (less than 0.3 g/10 g as a total sum with lactose), it is contraindicated in patients who require a low galactose diet.

ADVERSE REACTIONS 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. To report SUSPECTED ADVERSE REACTIONS, contact Apozeal Pharmaceuticals Inc. at 1-833-688-7848 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS 8.1 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. 8.3 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. 8.4 Pediatric Use Very little information on the use of lactulose in pediatric patients has been recorded. (See DOSAGE AND ADMINISTRATION.)

DESCRIPTION Lactulose is a synthetic disaccharide in solution form for oral administration. Each 15 mL of Lactulose Solution contains: 10 g lactulose (and less than 1.6 g galactose, less than 1.2 g lactose, and 1.2 g or less of other sugars). Also contains FD&C Blue No. 1, FD&C Yellow No. 6, purified water, and flavoring. Sodium hydroxide used to adjust pH. The pH range is 2.5 to 6.5. Lactulose is a colonic acidifier which promotes laxation. The chemical name for lactulose is 4-0-ß-D-galactopyranosyl-D-fructofuranose. The molecular formula is C 12 H 22 O 11 . It has the following structural formula: The molecular weight is 342.30. It is freely soluble in water. Chemical Structure

OVERDOSAGE 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 LD 50 : The acute oral LD 50 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. Its molecular similarity to sucrose, however, would suggest that it should be dialyzable.

HOW SUPPLIED NDC 0121-0577-08: 8 fl oz (237 mL) bottles NDC 0121-0577-16: 16 fl oz (473 mL) bottles NDC 0121-0577-32: 32 fl oz (946 mL) bottle NDC 0121-4577-15: 15 mL unit dose cup NDC 0121-4577-40: Case contains 40 unit dose cups of 15 mL (0121-4577-15) packaged in 4 trays of 10 unit dose cups each. NDC 0121-4577-06: Case contains 96 unit dose cups of 15 mL (0121-4577-15) packaged in 6 cartons of 16 unit dose cups each. NDC 0121-1154-30: 30 mL unit dose cup NDC 0121-1154-40: Case contains 40 unit dose cups of 30 mL (0121-1154-30) packaged in 4 trays of 10 unit dose cups each. NDC 0121-1154-00: Case contains 100 unit dose cups of 30 mL (0121-1154-30) packaged in 10 trays of 10 unit dose cups each. NDC 0121-1154-06: Case contains 96 unit dose cups of 30 mL (0121-1154-30) packaged in 6 cartons of 16 unit dose cups each. Lactulose solution contains lactulose 667 mg/mL (10 g/15 mL). Store at controlled room temperature, 20°-25°C (68°-77°F). [See USP] Do not freeze. 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 30°C (86°F) 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. Keep tightly closed. Dispense in original container or tight, light-resistant container with a child-resistant closure. To the Pharmacist: When ordering this product, include the product number (or NDC) in the description.