Urophoscin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT UROFOSCINâ (UROFOSCIN)

Composition:

Active substance: fosfomycin;

1 sachet contains 5.631 g of fosfomycin trometamol, equivalent to 3 g of fosfomycin;

Excipients: orange flavor, mandarin flavor, sodium saccharin, sucrose.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: granular powder of white or almost white color with a characteristic odor of mandarin flavor.

Pharmacotherapeutic group.

Antibacterials for systemic use. Other antibacterials.

ATC code J01X X01.

Pharmacological properties.

Urophoscinâ 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 of peptidoglycan synthesis.

Pharmacodynamics.

Urophoscinâ 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 affects 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 may also reduce 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. The 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 isolated in urinary tract infections.

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

A large proportion of multidrug-resistant E. coli and other extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are susceptible to fosfomycin. Similarly, most strains of methicillin-resistant Staphylococcus aureus (MRSA) are also 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 causing urinary tract infections, as well as penicillinase-producing strains.

In vivo, susceptibility is observed against Enterobacter spp., Klebsiella spp., Enterococci, Proteus mirabilis, Staph. aureus, and Staph. saprophyticus.

In addition, Urophoscinâ reduces bacterial adhesion to the urothelial mucosal epithelium, which may be a triggering factor for recurrent infections.

Pharmacokinetics

Absorption

After oral administration, approximately 50% of fosfomycin trometamol is rapidly absorbed. Following a dose of 50 mg/kg body weight, the time to reach maximum concentration (tmax) is 2–2.5 hours, and the maximum concentration (Cmax) 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 groups

In patients with renal impairment, drug elimination is slowed in proportion to the degree of functional impairment, and the plasma elimination half-life (t1/2) is prolonged (up to 50 hours when creatinine clearance is 10 mL/min).

Clinical characteristics.

Indications.

Treatment of acute uncomplicated lower urinary tract infections caused by microorganisms sensitive to fosfomycin in males, girls aged 12 years and older, and women. Prophylaxis during diagnostic procedures and surgical interventions in adult patients.

Contraindications.

Hypersensitivity to the components of the drug, severe renal impairment (creatinine clearance <10 ml/min), age under 12 years, undergoing hemodialysis.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration with metoclopramide and other drugs that increase gastrointestinal motility reduces absorption of Urofoscin®, resulting in decreased concentrations of Urofoscin® in serum and urine.

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 is difficult to determine whether changes in INR are related to the infectious disease itself or caused by drug administration. However, certain classes of antibiotics are more frequently associated with INR fluctuations, including fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Interaction studies were conducted only in adults.

Special precautions for use

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

Administration of phosphomycin may lead to hypersensitivity reactions, including anaphylaxis and anaphylactic shock, which may be life-threatening (see section "Adverse reactions").

If such reactions occur, phosphomycin should be discontinued immediately, and re-administration of phosphomycin to these patients is contraindicated. Appropriate therapeutic measures should be initiated.

Concomitant food intake slows the absorption of phosphomycin. Therefore, it is recommended to administer the drug on an empty stomach or 2–3 hours after eating.

Antibiotic use, including trometamol salt of phosphomycin, may lead to antibiotic-associated diarrhea. The severity may range from mild diarrhea to colitis with fatal outcome. Development of severe, persistent and/or bloody diarrhea during or after (including several weeks after) completion of antibiotic therapy may indicate Clostridium difficile-associated diarrhea (CDAD). Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after treatment with trometamol phosphomycin. If CDAD is suspected or confirmed, appropriate therapy should be initiated immediately. In such cases, drugs that inhibit intestinal motility are contraindicated.

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

Urofoscin® contains sucrose. Diabetic patients and those requiring dietary restrictions should be aware that one sachet of Urofoscin® contains 2.213 g of sucrose. Urofoscin® should not be administered to patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding

Pregnancy

Single-dose treatment of urinary tract infections with Urofoscin® is not considered appropriate during pregnancy.

Animal studies have not shown any direct or indirect adverse effects on pregnancy, embryonic development, fetal development, or postnatal development.

There are only limited data on the safety of phosphomycin use in pregnant women. These data do not indicate an increased risk of congenital malformations or fetal/neonatal toxicity associated with phosphomycin.

The use of the medicinal product during pregnancy is possible only if clearly needed, when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Urofoscin® is excreted in breast milk even after a single dose. The use of the drug should be discontinued during breastfeeding.

Ability to affect reaction rate while driving or operating machinery

Urofoscin® may cause dizziness, which may impair the ability to drive or operate machinery.

Method of Administration and Dosage

Urofoscinâ is administered orally on an empty stomach, preferably before bedtime, after emptying the urinary bladder. The contents of the sachet should be dissolved in one glass of water and the resulting solution should be consumed immediately.

Concomitant food intake slows down the absorption of fosfomycin. Therefore, it is advisable to take the medication on an empty stomach or 2–3 hours after a meal.

The medicinal product in this dosage (3 g) is indicated for patients with a body weight of 50 kg or more.

Treatment
Adults and adolescents with body weight ≥ 50 kg: one sachet of Urofoscinâ 3 g once daily.
Prophylaxis

Adults with body weight ≥ 50 kg: one sachet of Urofoscinâ 3 g 3 hours before and 24 hours after the procedure.

Children

The medication may be used for the treatment of acute uncomplicated lower urinary tract infections in girls aged 12 years and older.

There is insufficient data on the therapeutic use of the drug in boys aged 12 years and older, as well as on prophylactic use in both boys and girls.

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 associated with a single dose of fosfomycin trometamol are gastrointestinal disorders, primarily diarrhea. These events are usually transient and resolve spontaneously.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Reporting of adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 1.5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 8 g in sachets. 1 sachet per cardboard pack.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business. 139 Saksahanskoho Street, Kyiv, 01032, Ukraine.