Lactulose

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LACTULOSE (LACTULOSE)

Composition:
Active substance: lactulose (in the form of liquid lactulose);
1 ml of syrup contains lactulose (as liquid lactulose) — 670 mg;
Excipients: none.

Pharmaceutical form: Syrup.

Main physicochemical properties: Clear, viscous liquid, ranging from colorless to yellowish-brown.

Pharmacotherapeutic group: Osmotic laxatives.
ATC code: A06AD11.

Pharmacological properties

Pharmacodynamics:
In the large intestine, lactulose is broken down by intestinal bacteria into low-molecular-weight organic acids. These acids lower the pH in the lumen of the colon and, through an osmotic effect, increase the volume of intestinal contents. This stimulates colonic peristalsis and normalizes stool consistency. Constipation is corrected, and the physiological rhythm of the intestine is restored.

In hepatic encephalopathy (or hepatic coma and precoma), the drug's action is due to inhibition of proteolytic bacterial growth as a result of increased numbers of acidophilic bacteria (e.g., lactobacilli), binding of ammonia in ionic form due to acidification of intestinal contents, cleansing of the colon due to low pH, as well as the osmotic effect and alteration of bacterial nitrogen metabolism by stimulating bacterial utilization of ammonia for bacterial protein synthesis.

In this context, however, it should be noted that neuropsychiatric manifestations of hepatic encephalopathy cannot be explained solely by hyperammonemia. Nevertheless, ammonia can be considered representative of other nitrogenous compounds.

As a prebiotic, lactulose enhances the growth of beneficial bacteria such as bifidobacteria and lactobacilli, while potentially suppressing the growth of pathogenic bacteria such as clostridia and Escherichia coli. This may lead to a more favorable balance of intestinal flora.

Pharmacokinetics:
Lactulose is almost not absorbed after oral administration and reaches the colon unchanged, where it is metabolized by the bacterial flora. When administered at doses of 25–50 g (or 40–75 ml), lactulose is completely metabolized. With higher doses, part of the lactulose may be excreted unchanged.

Clinical characteristics

Indications:

• Constipation: regulation of the physiological rhythm of the intestine.
• Conditions requiring easier defecation (hemorrhoids, postoperative period after surgery on the colon or anorectal zone).
• Hepatic encephalopathy: treatment and prevention of hepatic coma and precoma.

Contraindications

Hypersensitivity to the active substance; galactosemia; acute abdominal pain of unknown origin; nausea; vomiting; gastrointestinal obstruction/intestinal stenosis; rectal bleeding; gastrointestinal perforation or risk of gastrointestinal perforation; acute inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease; severe dehydration.

Interaction with other medicinal products and other forms of interaction:
If the patient is taking any other medicinal products, this must be reported to the physician. When used concomitantly with enteric-coated, pH-dependent release medicinal products, it should be remembered that lactulose lowers intestinal pH.
Concomitant use with broad-spectrum antibiotics or antacids may reduce the therapeutic efficacy of lactulose.
Lactulose may increase potassium loss induced by other medicinal products (e.g., thiazide diuretics, corticosteroids, and amphotericin B).
Potassium deficiency may enhance the effects of cardiac glycosides.
It is not recommended to take lactulose within 2 hours after taking other medicinal products.

Special precautions for use:
Consultation with a physician is recommended if:

• there is abdominal pain of undetermined origin before starting treatment;
• the therapeutic effect is insufficient after several days of treatment.

The dose usually used for treating constipation generally does not cause problems in patients with diabetes mellitus. However, the dose used for treating hepatic encephalopathy is usually much higher, and this should be taken into account when treating diabetic patients.

Long-term use of the medicinal product without dose adjustment or incorrect use may lead to diarrhea and electrolyte imbalance. In severe cases, dehydration or hypokalemia may develop. Hypokalemia may cause cardiac or neuromuscular dysfunction, particularly if the patient is concurrently receiving cardiac glycosides, diuretics, or corticosteroids. Regular monitoring of serum electrolyte levels is recommended, especially in elderly and debilitated patients.

This medicinal product contains lactose, galactose, and a small amount of fructose. Therefore, patients with rare hereditary intolerance to galactose or fructose, lactase deficiency, or glucose-galactose malabsorption should not take this product.

Lactulose should be used in patients with gastroesophageal reflux syndrome (Röhmel syndrome) only after consultation with a physician.

To prevent the occurrence of flatulence, it is recommended to gradually increase the dose. If flatulence occurs, the dose should be reduced or treatment discontinued.

If symptoms of disease do not begin to resolve, or if the condition worsens, or if adverse reactions occur, the use of the medicinal product must be discontinued and the patient should consult a physician regarding further treatment.

Use during pregnancy or breastfeeding

Pregnancy:
No adverse effects are expected during pregnancy, as the systemic effect of lactulose on the pregnant woman is negligible. Lactulose syrup may be used during pregnancy.

Breastfeeding:
No adverse effects are expected in the newborn/infant during breastfeeding, as the systemic effect of lactulose on the breastfeeding woman is negligible. Lactulose syrup may be used during breastfeeding.

Fertility:
No adverse effects are expected, as the systemic effect of lactulose is negligible.

Ability to affect reaction speed when driving or operating machinery:
Lactulose has no effect or has a negligible effect on the ability to drive a vehicle or operate complex machinery.

Method of administration and dosage:
Lactulose may be taken either diluted or undiluted. The dose should be adjusted according to individual patient needs. The single dose should be swallowed immediately and should not be held in the mouth for a prolonged period.

If the medicinal product is prescribed once daily, the dose should always be taken at the same time of day, for example, during breakfast.

During treatment with laxatives, it is recommended to consume sufficient fluid: 1.5–2 liters (approximately 6–8 glasses) per day.

Dosage for constipation or for softening stools for medical purposes

The dosing cup provided with the medicinal product should be used for measuring the dose. The daily dose of Lactulose can be taken once or divided into two doses. After a few days, the initial dose may be adjusted to a maintenance dose based on the response to treatment. A few days of therapy (2–3 days) may be required before the therapeutic effect becomes evident.

Dosage in hepatic encephalopathy (for adults only):
Initial dose: 30–45 mL, 3–4 times daily. This dose may be adjusted to a maintenance dose to achieve soft bowel movements 2 to 3 times per day.
The safety and efficacy of the medicinal product in children (from birth to 18 years of age) with hepatic encephalopathy have not been established. Data are lacking.

Elderly patients and patients with renal or hepatic impairment:
Since the systemic impact of lactulose is negligible, no specific dosage recommendations are required for these patient groups.

Children:
The use of laxatives in children should occur only in exceptional cases and requires medical supervision. There is no data on the use of the medicinal product in children with hepatic encephalopathy. It should be considered that the defecation reflex may be impaired during treatment.

Overdose:
If doses are too high, symptoms such as abdominal pain and diarrhea may occur. Recommended treatment includes discontinuation of the drug or dose reduction, and correction of electrolyte imbalances caused by excessive fluid loss due to diarrhea or vomiting. If symptoms of overdose persist, immediate medical attention is required.

Adverse reactions:
During the first few days of treatment, flatulence may occur, which usually resolves after a few days. When the drug is used at doses exceeding the recommended ones, abdominal pain and diarrhea may occur. In such cases, the dose should be reduced. With prolonged use of high therapeutic doses (usually only in patients with hepatic encephalopathy), electrolyte imbalance due to diarrhea may be observed.

During post-marketing use, hypersensitivity reactions have been reported, mostly limited to skin manifestations, which have been identified as possible adverse reactions. Since these reactions were reported spontaneously and the size of the patient population is not known, the frequency of these reactions cannot be reliably estimated.

The frequency of adverse reactions is defined according to the following classification: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated based on available data).

Children. The safety profile in children is expected to be the same as in adults. Reporting of adverse reactions after marketing authorization is important. This enables monitoring of the benefit-risk balance when using this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua. Shelf life. 4 years. Shelf life after opening the bottle — 2 months at a temperature not exceeding 25 ºC. Storage conditions. Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach of children. Do not freeze due to the tendency of lactulose to crystallize. Packaging. 200 ml, 300 ml, or 500 ml in a bottle; 1 bottle with a dosing cup in a carton. Category of release. Over-the-counter. Manufacturer. LLC "DKP "Pharmaceutical Factory". Manufacturer's address and location of business activity: 4 Korolova St., Stanishivka village, Zhytomyr district, Zhytomyr region, 12430, Ukraine.