Enterogermina®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENTEROGERMINA®

Composition:

Active substance: 1 capsule contains a mixture of spores of the polyresistant strain Bacillus clausii 2 × 10⁹;

Excipients: microcrystalline cellulose, magnesium stearate;

capsule shell: gelatin, titanium dioxide (E 171), purified water.

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard white gelatin capsules containing a fine powder ranging in color from whitish to ivory.

Pharmacotherapeutic group. Anti-diarrheal microbial agents. ATC code A07FA.

Pharmacological Properties

Pharmacodynamics

Enterogermina® is a suspension of spores of four 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 capable of withstanding high temperatures and gastric acidity. In a validated in vitro model, Bacillus clausii spores demonstrated the ability to survive in a simulated gastric environment (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 after a single oral dose.

Due to the action of Bacillus clausii, the medicinal product restores intestinal microflora altered by medications that cause dysbacteriosis (also known as dysbiosis), which may also be associated with gastrointestinal symptoms such as diarrhea, abdominal pain, and increased intestinal gas. Thanks to the metabolic activity of Bacillus clausii, the use of the product enables achieving nonspecific antagonistic and antitoxic effects.

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

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

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

A prospective, multicenter, observational 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, flatulence, constipation, and abdominal discomfort. Assessment was based on patient questionnaires administered by pharmacists before the start of treatment and 30 days after its initiation.

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

The average duration of treatment was 7.1 days. Patients reported symptom improvement on average after three days of treatment. After completion of treatment, 95% of patients reported a reduction in diarrhea, and 97% reported relief from abdominal pain.

The two main mechanisms described below contribute to the effect of Bacillus clausii in restoring intestinal bacterial flora.

Inhibition of Pathogenic Bacterial Growth

Three likely mechanisms of action of B. clausii are: colonization of vacant ecological niches, thereby preventing the growth of other microorganisms; competition for binding to epithelial cells, particularly relevant for spores in the early and intermediate stages 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 including Staphylococcus aureus, Clostridium difficile, and Enterococcus faecium.

Immunomodulatory Activity

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

Pharmacokinetics

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

Furthermore, due to the ability of Bacillus clausii to synthesize various vitamins, particularly those of the B group, the product contributes to the correction of vitamin deficiency (avitaminosis) caused by the use of antibiotics or chemotherapeutic agents.

Clinical characteristics.

Indications.

• Treatment and prevention of intestinal dysbiosis and associated endogenous vitamin deficiency.
• Adjunctive therapy aimed at restoring normal intestinal microflora disrupted during treatment with antibiotics or chemotherapeutic agents.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Children under 5 years of age inclusive.

Interaction with other medicinal products and other forms of interaction.

There is no data available on interactions of the medicinal product with other medicinal products.

Special precautions for use.

The medicinal product has a high degree of heterologous resistance to antibiotics, which allows it to be used both for the prevention of intestinal microflora changes caused by the selective action of antibiotics (especially broad-spectrum antibiotics) and for the restoration of already disrupted intestinal microflora 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 contraindicated. 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 in preterm infants. In some severely ill patients, the outcome was fatal. This medicinal product should be avoided in these patient groups (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Pregnancy. Available data on the use of Enterogermina® capsules in pregnant women are limited; therefore, no conclusions can be drawn regarding the safety of the medicinal product during pregnancy.

Enterogermina® 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® capsules during breastfeeding, particularly regarding the presence of the medicinal product in breast milk and its effects on the infant, are limited; therefore, no conclusions can be drawn regarding the safety of the medicinal product during breastfeeding.

Enterogermina® 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® on human fertility.

Ability to affect reaction speed when driving or operating machinery. Enterogermina® does not affect the ability to drive or operate machinery.

Dosage and Administration

Adults – 2–3 capsules per day;
Children aged 5 years and older – 1–2 capsules per day.

Swallow capsules whole with a small amount of water or another beverage.

If a patient has difficulty swallowing solid capsules (especially young children), it is preferable to use an oral suspension.

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

Children. The drug is indicated for children aged 5 years and older.
Children under 5 years of age should be administered the drug in the form of an oral suspension.

Overdose.

There have been no reports to date of clinical manifestations of overdose with this drug.

Adverse reactions

The adverse reactions observed during the use of Enterogermina® 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 and urticaria, angioneurotic edema.

Infections and infestations

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy of the medicine via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Keep out of the reach of children.

Store at a temperature not exceeding 30 °C.

Packaging. No. 12, No. 24 (12 × 2): 12 capsules per blister, 1 or 2 blisters per cardboard box.

Supply classification. Over-the-counter.

Manufacturer.

Opella Helcea Italia S.r.l.

Manufacturer's address.

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

Marketing Authorization Holder.

LLC "Opella Helcea Ukraine", Ukraine.

Address of the Marketing Authorization Holder.

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