Fonurol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FONUROL® (FONUROL)

Composition:

Active substance: fosfomycin;

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

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

Pharmaceutical form. Granules for oral solution.

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

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Other antimicrobial agents.

ATC code J01X X01.

Pharmacological properties.

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

Pharmacodynamics.

Fonurol*®* 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 analogous to that of phosphoenolpyruvate. Therefore, it inactivates the enzyme enolpyruvyl transferase, thereby irreversibly blocking the condensation of uridinediphosphate-N-acetylglucosamine with phosphoenolpyruvate, one of the initial steps 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 bacterial species may develop resistance. The resistance rate of E. coli causing uncomplicated urinary tract infections is extremely low.

Most multidrug-resistant E. coli and other extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae remain susceptible to fosfomycin. Likewise, the majority of methicillin-resistant Staphylococcus aureus (MRSA) strains 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 from all other antibiotics in its chemical structure 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 penicillinase-producing strains.

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

In addition, fosfomycin reduces bacterial adhesion to the urothelial epithelium, which may be a contributing factor in the development of recurrent urinary tract infections.

Pharmacokinetics.

Absorption

After oral administration, approximately 50% of fosfomycin trometamol is rapidly absorbed. Following 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.

Excretion

The plasma elimination half-life is approximately 4 hours. After a single 3 g dose of fosfomycin trometamol, concentrations in urine 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 administered 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 in proportion to the degree of functional impairment, and plasma elimination half-life is prolonged (t_1/2 up to 50 hours at a creatinine clearance of 10 mL/min).

Clinical characteristics.

Indications.

Treatment of acute uncomplicated cystitis in women and girls aged 12 years and older. 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 or to other components of the drug, severe renal impairment (creatinine clearance < 10 mL/min), pediatric age under 12 years, undergoing hemodialysis.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration with metoclopramide and other agents that enhance gastrointestinal motility reduces absorption of fosfomycin, leading to decreased concentrations of the medicinal product Fonurol*®* in serum and urine.

When the drug 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 problems related to fluctuations in the international normalized ratio (INR). Numerous cases of increased antagonistic activity of vitamin K antagonists have been reported in patients taking antibiotics. Risk factors include: severe infections or inflammatory conditions, advanced age, and poor general health status. In such cases, it is difficult to determine whether the change in INR is associated with the infectious disease itself or caused by drug intake. However, certain classes of antibiotics are more frequently linked to INR fluctuations, particularly: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Interaction studies have been conducted only in adults.

Special precautions for use

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

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

The use of antibiotics, including trometamol fosfomycin, may lead to antibiotic-associated diarrhea. The severity may range from mild diarrhea to fatal colitis. The 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 fosfomycin. If CDAD is suspected or confirmed, appropriate therapy should be initiated immediately. In such cases, drugs that inhibit peristalsis are contraindicated.

Renal impairment: Therapeutically effective concentrations of fosfomycin in urine are maintained for up to 48 hours if creatinine clearance is above 10 mL/min.

The product contains sucrose. Patients with diabetes mellitus or those requiring a special diet should be aware that each sachet contains 2.213 g of sucrose. Fosfomycin is contraindicated in patients with fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

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

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, or postnatal development.

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

Fosfomycin may be used during pregnancy only if clearly needed, when the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding

Fosfomycin is excreted in breast milk even after a single dose. Therefore, the use of this medicinal product is not recommended during breastfeeding.

Ability to affect driving and use of machines

Fosfomycin may cause dizziness, which may affect the ability to drive or operate machinery.

Dosage and Administration.

FonuroL*®* is taken orally on an empty stomach, preferably at bedtime, after emptying the urinary bladder. The contents of the sachet should be dissolved in one glass of water and the prepared solution should be consumed immediately.

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

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

Treatment
Adults and adolescents with a body weight of 50 kg and above: one sachet of FonuroL*®* 3 g once daily.

Prophylaxis
Adults with a body weight of 50 kg and above: one sachet of FonuroL*®* 3 g 3 hours before and 24 hours after the procedure.

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, hearing impairment, metallic taste in the mouth, and general reduction in taste perception.

Cases of arterial hypotension, severe drowsiness, electrolyte imbalances, 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 disturbances, primarily diarrhea. These events are usually transient and resolve spontaneously.

The table below lists the adverse reactions observed in clinical trials or reported from post-marketing experience.

The frequency of adverse effects 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);
not known (cannot be estimated from the available data).

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

Reporting of adverse reactions

It is important to report adverse reactions following the registration of medicinal products. This enables ongoing monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

Sachets made of laminated foil. 1 sachet per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ASTRAFARM LLC, Ukraine.

Manufacturer's address and location of its business operations.

6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Region, 08132, Ukraine.