ENTEROGERMINA® FORTE

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENTEROGERMINA® FORTE

Composition:

Active substance: spores of the polyresistant strain Bacillus clausii;

1 vial of 5 ml contains spores of the polyresistant strain Bacillus clausii 4 × 10⁹;

Excipient: purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: white opalescent liquid.

Pharmacotherapeutic group. Antidiarrheal microbial agents.

ATC code A07F A.

Pharmacological Properties.

Pharmacodynamics.

Enterogermina® Forte is a suspension containing spores of 4 strains (SIN, O/C, T, N/R) of Bacillus clausii, which are normally present in the intestine and do not exhibit pathogenic activity.

Spores are inherently resistant to high temperatures and gastric acidity. In a validated in vitro model, Bacillus clausii spores demonstrated the ability to survive in an environment simulating gastric conditions (pH 1.4–1.5) for up to 120 minutes (survival rate 96%). In a model simulating intestinal conditions (bile salts and pancreatin solution – pH 8), Bacillus clausii spores demonstrated the ability to multiply significantly compared to the initial count (from 10^9 to 10^12 colony-forming units (CFU)), starting from 240 minutes after incubation. In a study involving 20 subjects, it was observed that Bacillus clausii spores persist in the human intestine and can be detected in feces for up to 12 days following a single oral dose.

Due to the action of Bacillus clausii, the medicinal product restores intestinal microflora altered by drug therapy leading to dysbacteriosis (also known as dysbiosis), which may also be associated with gastrointestinal symptoms such as diarrhea, abdominal pain, and meteorism (intestinal bloating). Additionally, due to the ability of Bacillus clausii to synthesize various vitamins, particularly those of the B group, the product helps correct vitamin deficiencies caused by the use of antibiotics or chemotherapeutic agents. Thanks to the metabolic activity of Bacillus clausii, the use of the product achieves a nonspecific antigenic and antitoxic effect.

Due to their high resistance to chemical and physical agents, Bacillus clausii spores pass unharmed through the gastric juice barrier into the intestinal tract, where they transform into metabolically active vegetative cells.

In two open, randomized, controlled clinical trials, the medicinal product Enterogermina® Forte demonstrated a reduction in the duration of acute diarrhea in children aged 6 months and older.

When administered during antibiotic treatment and for the subsequent 7–10 days, Enterogermina® Forte demonstrated a reduction in the frequency of abdominal pain and diarrhea associated with antibiotic use.

A prospective, observational, multicenter study included 261 patients to evaluate the use of the probiotic Bacillus clausii under real-life conditions for symptoms such as diarrhea, abdominal pain, bloating, meteorism, constipation, and abdominal discomfort. The evaluation was based on patient questionnaires administered by pharmacists before the start of treatment and 30 days after its initiation.

Patients reported using the product primarily to treat diarrhea (56.7% of patients), abdominal pain (13.41%), and bloating (12.64%).

The average treatment duration was 7.1 days. Patients reported symptom improvement after an average of three days of using the medicinal product. After completion of treatment, 95% of patients reported reduced diarrhea, and 97% reported relief from abdominal pain.

The two main properties of Bacillus clausii described below contribute to the restoration of intestinal bacterial flora.

Inhibition of pathogenic bacterial growth

Three likely mechanisms of action of B. clausii are: colonization of free ecological niches, thereby preventing the growth of other microorganisms; competition for binding to epithelial cells, particularly relevant for spores in the early and intermediate phases of germination; and production of antibiotics and/or enzymes secreted into the intestinal environment. In an in vitro study, Bacillus clausii spores demonstrated the production of bacteriocins and antibiotics such as clausin, with antagonistic activity against gram-positive bacteria Staphylococcus aureus, Clostridium difficile, and Enterococcus faecium.

Immunomodulatory activity

Orally administered Bacillus clausii spores demonstrated stimulation of interferon-gamma production and increased proliferation of CD4+ T-lymphocytes in in vitro and in vivo mouse models.

Pharmacokinetics.

The product does not interact with the following antibiotics: penicillin (when not used in combination with beta-lactamase inhibitors), cephalosporins (partial resistance in most cases), tetracyclines, macrolides, aminoglycosides (except gentamicin and amikacin), chloramphenicol, thiamphenicol, lincomycin, clindamycin, isoniazid, cycloserine, novobiocin, rifampicin, nalidixic acid, and pipemidic acid (intermediate resistance), metronidazole.

Clinical characteristics.

Indications.

Treatment and prevention of intestinal dysbacteriosis and associated endogenous vitamin deficiency.

Adjunctive therapy aimed at restoring normal intestinal microflora disrupted during treatment with antibiotics or chemotherapeutic agents.

Acute and chronic gastrointestinal disorders in infants associated with intoxication or intestinal dysbacteriosis and vitamin deficiency.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

Special precautions for use

Visible particles may be present in bottles of Enterogermina® Forte, which are formed due to aggregation of Bacillus clausii spores and do not indicate that the product has undergone any changes.

The bottle should be shaken well before use.

The medicinal product has a high degree of heterologous antibiotic resistance, allowing it to be used both for prophylaxis of antibiotic-induced intestinal flora alterations (especially those caused by broad-spectrum antibiotics) and for restoration of already disrupted intestinal microbial balance.

If the medicinal product is prescribed concomitantly with antibiotics, it should be administered between two doses of the antibiotic.

This medicinal product is intended exclusively for oral administration. Parenteral or any other route of administration is strictly prohibited. Incorrect use of this medicinal product has led to severe anaphylactic reactions, including anaphylactic shock.

Bacteraemia and sepsis

Post-marketing cases of bacteraemia, septicaemia, and sepsis have been reported in immunocompromised patients, critically ill patients, and premature infants. In some severely ill patients, the outcome was fatal. Administration of Enterogermina® Forte should be avoided in these patient groups (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Pregnancy. Available data on the use of Enterogermina® Forte in pregnant women are limited; therefore, a conclusion on safety during pregnancy cannot be made.

Enterogermina® Forte may be used during pregnancy only if the potential benefit to the pregnant woman outweighs the potential risks, including risks to the fetus.

Breastfeeding. Available data on the use of Enterogermina® Forte during breastfeeding, particularly regarding its presence in breast milk and effects on the infant, are limited; therefore, conclusions on safety during breastfeeding cannot be made.

Enterogermina® Forte may be used during breastfeeding only if the potential benefit to the mother outweighs the potential risks, including risks to the breastfed infant.

Fertility. There are no data available on the effect of Enterogermina® Forte on human fertility.

Ability to influence reaction speed when driving vehicles or operating machinery

Enterogermina® Forte does not affect the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

The contents of the vial are taken undiluted or diluted in water or other beverages (e.g., milk, tea, or orange juice). This medicinal product is intended for oral use only. Do not administer parenterally or by any other route.

Dosage for adults: 5 ml (1 vial) per day.

Children. The preparation may be used in children from 28 days of age. The recommended dose for infants and children is 5 ml (1 vial) per day.

The duration of treatment is determined by the physician depending on the patient's condition and the course of the disease:

• Treatment and prevention of intestinal dysbiosis and associated endogenous vitamin deficiency – 5–7 days;
• Adjunctive therapy aimed at restoring normal intestinal microflora disrupted during treatment with antibiotics or chemotherapeutic agents – throughout the course of antibiotic therapy (on average, 5–10 days);
• Acute and chronic gastrointestinal disorders in infants associated with intoxication, intestinal dysbiosis, and vitamin deficiency: acute – 5–7 days; chronic – up to 30 days.

Overdose.

No cases of overdose have been reported.

Side effects

The side effects reported during the use of Enterogermina® Forte are listed below, classified by system organ class and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Skin and subcutaneous tissue disorders

Frequency not known: hypersensitivity reactions, including rash, urticaria, and angioedema.

Infections and infestations

Frequency not known: bacteremia, septicemia, and sepsis (in patients with weakened immune systems or critically ill patients) (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store out of reach of children at a temperature below 30 °C.

To avoid contamination of the suspension, do not open the vial in advance.

Packaging.

No. 5: 5 mL in a vial; 5 vials connected by a polyethylene bridge in a cassette, in a cardboard box.

No. 10; No. 20 (10 × 2): 5 mL in a vial; 10 vials connected by a polyethylene bridge in a cassette; 1 or 2 cassettes in a cardboard box.

Category of supply. Over-the-counter.

Manufacturer.

Opella Healthca Italia S.r.l.

Manufacturer's address.

Viale Europa, 11 – 21040 Origgio (VA), Italy.

Marketing Authorization Holder.

LLC "Opella Healthca Ukraine", Ukraine.

Address of the Marketing Authorization Holder.

Ukraine, 01033, Kyiv, Zhilyanska St., 48-50A.