EVROMYCIN

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROMYCIN (EUROMYCIN)

Composition:

Active substance: fosfomycin;

1 sachet contains 5.631 g of fosfomycin trometamol, equivalent to 3.0 g of fosfomycin;

Excipients: lemon flavoring, sodium saccharin (E 954), sucrose.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white granular powder. After dissolution, a characteristic citrus aroma is noticeable.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other antimicrobials. Fosfomycin.

ATC code J01X X01.

Pharmacological properties.

Euromicin contains the active substance fosfomycin in the form of fosfomycin trometamol salt. Fosfomycin is a bactericidal antibiotic (a derivative of phosphonic acid). It inhibits bacterial cell wall synthesis by blocking one of the initial steps in peptidoglycan synthesis.

Pharmacodynamics.

Euromicin contains fosfomycin [mono (2-amino-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxiranyl) phosphonate], an antibiotic derived from phosphonic acid, used for the treatment of urinary tract infections.

Fosfomycin acts on the first stage of bacterial cell wall synthesis.

The structure of fosfomycin is similar to that of phosphoenolpyruvate. Therefore, it inactivates the enzyme enolpyruvyl transferase, thereby irreversibly blocking the condensation of uridine diphosphate-N-acetylglucosamine with phosphoenolpyruvate—one of the initial stages in bacterial cell wall synthesis. Fosfomycin also reduces bacterial adhesion to the urothelial mucosa, which may be a triggering factor in the development of recurrent infections.

The table below presents in vitro activity data of fosfomycin trometamol against clinically isolated microorganisms. Minimal inhibitory concentration (MIC) was determined by the disk-diffusion method using fosfomycin trometamol 200 μg disks. Microorganisms with a diameter of complete inhibition zone > 16 mm (on Mueller-Hinton medium) were classified as susceptible (corresponding to 200 μg/mL).

Resistance / Cross-resistance

Fosfomycin retains its efficacy against the most common bacteria causing urinary tract infections.

Only a few bacteria may develop resistance. The resistance rate of E. coli causing uncomplicated urinary tract infections is extremely low.

A large proportion of multidrug-resistant E. coli and other extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are susceptible to fosfomycin. Likewise, most strains of methicillin-resistant Staphylococcus aureus are susceptible to fosfomycin.

To date, no cases of cross-resistance with other antibacterial agents have been reported. Cross-resistance is unlikely because fosfomycin differs chemically from all other antibiotics and has a unique mechanism of action.

Clinical efficacy

Fosfomycin has a broad spectrum of antibacterial activity, including against most Gram-positive and Gram-negative microorganisms responsible for urinary tract infections, as well as against strains producing penicillinase.

In vivo, resistance has been observed in Enterobacter spp., Klebsiella spp., Enterococcus, Proteus mirabilis, Staph. aureus, and Staph. saprophyticus.

In addition, Euromycin reduces bacterial adhesion to the urothelial mucosa of the urinary bladder, which may be a triggering factor for recurrent infections.

Pharmacokinetics.

Absorption

After oral administration, approximately 50% of fosfomycin trometamol is rapidly absorbed. After a dose of 50 mg/kg body weight, t_max is 2–2.5 hours and C_max is 20–30 μg/mL.

Distribution

Plasma protein binding of fosfomycin is very low (less than 5%). The volume of distribution is 1.5–2.4 L/kg body weight.

Fosfomycin crosses the placental barrier and is excreted into breast milk.

Metabolism

Fosfomycin is not metabolized.

Elimination

The plasma elimination half-life is approximately 4 hours. After a single 3 g dose of fosfomycin trometamol, urinary concentrations of 1800–3000 μg/mL are achieved within 2–4 hours. Therapeutically effective concentrations (200–300 μg/mL) are maintained for up to 48 hours after administration. 40–50% of the dose is excreted unchanged in urine within the first 48 hours.

Pharmacokinetics in special patient populations

In patients with renal impairment, drug elimination is slowed proportionally to the degree of functional impairment, and the plasma elimination half-life is prolonged (t_1/2 up to 50 hours when creatinine clearance is 10 mL/min).

Clinical characteristics.

Indications.

For the treatment of acute uncomplicated cystitis in women and girls aged 12 years and older.

For the prevention of infections in adult men undergoing transrectal prostate biopsy.

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications. Hypersensitivity to fosfomycin and other components of the medicinal product, severe renal impairment (creatinine clearance < 10 ml/min), pediatric age under 12 years, undergoing hemodialysis.

Interaction with other medicinal products and other types of interactions.

Concomitant administration with metoclopramide and other drugs that increase gastrointestinal (GI) motility reduces the absorption of Euromycin, resulting in decreased fosfomycin concentrations in serum and urine.

When the medicinal product is taken with food, plasma and urinary levels of fosfomycin are reduced. Therefore, it is recommended to take the medicinal product on an empty stomach or 2–3 hours after eating or taking other medications.

Specific issues regarding fluctuations in INR (International Normalized Ratio). Numerous cases of increased antagonistic activity of vitamin K antagonists have been reported in patients taking antibiotics. Risk factors include: severe infections or inflammation, advanced age, and poor general health status. In such cases, it may be difficult to determine whether changes in INR are related to the infectious disease or caused by the drug. However, certain classes of antibiotics are more frequently associated with INR fluctuations, including: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Interaction studies have been conducted only in adults.

Special precautions for use

There is insufficient evidence of efficacy of the use of Euromicin in children. Since the 3 g dose is not intended for children under 12 years of age, Euromicin should not be used in this age group.

Use of fosfomycin may lead to development of hypersensitivity reactions, including anaphylaxis and anaphylactic shock, which may be life-threatening (see section "Side effects").

In case of development of such reactions, administration of fosfomycin should be discontinued and re-administration of fosfomycin to these patients is contraindicated. Appropriate therapeutic measures should be initiated.

Use of antibiotics, including trometamol fosfomycin, may lead to diarrhea. Severity may vary from mild diarrhea to colitis with fatal outcome. Severe, persistent and/or bloody diarrhea during or after completion of antibiotic treatment (even several weeks later) may be a symptom of Clostridium difficile-associated diarrhea. Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after taking trometamol fosfomycin. If there is suspicion or confirmation of the diagnosis, appropriate treatment should be initiated immediately. In such cases, drugs that inhibit peristalsis are contraindicated.

Renal impairment: the concentration of fosfomycin in urine remains therapeutically effective for 48 hours if creatinine clearance is above 10 ml/min.

Persistent infections and male patients: in case of persistent infections, thorough examination and re-evaluation of diagnosis are recommended, as this is often associated with complications of urinary tract infections or spread of resistant pathogens (e.g., Staphylococcus saprophyticus, see section "Pharmacodynamics"). Generally, urinary tract infections in male patients should be considered as complicated urinary tract infections, for which this medicinal product is not indicated (see section "Indications").

Euromicin contains sucrose. Patients with diabetes mellitus and those who need to follow a special diet should be aware that 1 sachet of Euromicin contains 2.213 g of sucrose. Euromicin should not be used in patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding

Pregnancy

Single-dose treatment of urinary tract infections in pregnant women is not considered appropriate.

Animal studies have not revealed any direct or indirect toxic effects on pregnancy, embryonal development, fetal development and/or postnatal development.

There are only limited data on the safety of fosfomycin use in pregnant women. These data do not indicate development of congenital malformations or fetal/neonatal toxicity of fosfomycin.

During pregnancy, the use of the medicinal product may be considered if necessary, when the expected benefit of therapy for the pregnant woman outweighs the potential risk to the fetus.

Lactation

Euromicin is excreted in breast milk even after a single dose. Use of the medicinal product should be discontinued during breastfeeding.

Ability to influence the speed of reactions when driving or operating machinery. Euromicin may cause dizziness, which may affect the ability to drive or operate machinery.

Method of Administration and Dosage

Acute uncomplicated cystitis treatment

For adult women and girls aged 12 years and older with body weight of 50 kg or more, the recommended dose is 1 sachet (3 g) of the medicinal product once daily.

Prophylaxis of infections in adult men undergoing transrectal prostate biopsy

For men with body weight of 50 kg or more, the recommended dose is 1 sachet (3 g) administered 3 hours before and 24 hours after the procedure.

Method of Administration

For oral use.

For treatment of acute uncomplicated cystitis in women and girls aged 12 years and older, the dose should be taken on an empty stomach (approximately 2–3 hours before or 2–3 hours after meals), preferably at bedtime and after emptying the bladder.

The contents of the sachet should be dissolved in one glass of water and the prepared solution should be taken immediately.

Children

The drug is indicated for girls aged 12 years and older for the treatment of acute uncomplicated cystitis.

Safety and efficacy of fosfomycin in children under 12 years of age have not been established.

Overdose

Data on fosfomycin overdose following oral administration are limited.

Symptoms: vestibular disturbances, impaired hearing, metallic taste in the mouth, and general reduction in taste perception.

Cases of hypotension, severe drowsiness, electrolyte disturbances, thrombocytopenia, and hypoprothrombinemia have been reported following parenteral administration of fosfomycin.

Treatment: symptomatic and supportive therapy. It is recommended to increase fluid intake to enhance diuresis.

Adverse reactions.

The most common adverse reactions following a single dose of fosfomycin trometamol are gastrointestinal disorders, predominantly diarrhea. These events are usually transient and resolve spontaneously.

The table below lists adverse reactions that have been reported in clinical trials or from post-marketing experience.

The frequency of adverse effects is defined as follows:

very common (≥ 1/10);

common (≥ 1/100 — < 1/10);

uncommon (≥ 1/1000 — < 1/100);

rare (≥ 1/10,000 — < 1/1000);

very rare (< 1/10,000);

unknown (cannot be estimated from the available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Reporting of suspected adverse reactions

Reporting of adverse reactions following the marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are requested to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use after the expiry date.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 8 g of the product (3 g of active substance) in sachets. 1 or 2 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and site of operations. 1 Gordienkovska Street, Kharkiv, Kharkiv region, 61010, Ukraine.