Fosfomycin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOSFOMYCIN

Composition:

Active substance: fosfomycin;

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

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

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white granular powder with a characteristic citrus aroma.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Other antimicrobial agents.

ATC code J01X X01.

Pharmacological properties.

The medicinal product 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 stages of peptidoglycan synthesis.

Pharmacodynamics.

The medicinal product 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 can trigger 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 zone diameter of complete inhibition > 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 can 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. Similarly, 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 chemically from all other antibiotics and has a unique mechanism of action.

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

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

In addition, the drug reduces bacterial adhesion to the urothelial mucosa, which may contribute to the development of recurrent 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 elimination half-life from plasma 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 in proportion 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 or to any of the 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 forms of interaction.

Concomitant administration with metoclopramide and other medicinal products that increase gastrointestinal motility reduces fosfomycin absorption, resulting in decreased drug concentrations in plasma and urine.

When the medicinal product is taken during meals, fosfomycin levels in blood plasma and urine are reduced. Therefore, it is recommended to take the medicinal product on an empty stomach or 2–3 hours after eating or taking other medicinal products.

Specific issues regarding fluctuations in INR (International Normalized Ratio). There have been reports of numerous cases of increased antagonistic effect of vitamin K antagonists 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 related to the infectious disease itself or caused by the medicinal product. However, use of certain classes of antibiotics is more frequently associated with INR fluctuations, particularly: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Interaction studies have been conducted only in adult patients.

Special precautions for use.

Hypersensitivity reactions. Serious and sometimes fatal hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during treatment with fosfomycin (see sections "Contraindications" and "Adverse reactions"). If such reactions occur, fosfomycin therapy should be discontinued immediately and appropriate emergency measures should be taken.

Clostridioides difficile-associated diarrhea. Cases of Clostridioides difficile-associated colitis and pseudomembranous colitis have been reported during fosfomycin use, with severity ranging from mild to life-threatening (see section "Special precautions for use"). This diagnosis should therefore be considered in patients who develop diarrhea during or after fosfomycin therapy. Discontinuation of fosfomycin therapy and initiation of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be used.

Pediatric patients. The safety and efficacy of fosfomycin in children under 12 years of age have not been established. Therefore, the medicinal product should not be used in this age group (see section "Posology and method of administration").

Persistent infections. Male patients. In cases of persistent infections, careful examination and reassessment of diagnosis are recommended, as these are often associated with complicated urinary tract infections or the spread of resistant pathogens (e.g., Staphylococcus saprophyticus, see section "Pharmacodynamics"). In general, urinary tract infections in male patients should be considered complicated urinary tract infections, for which this medicinal product is not indicated (see section "Therapeutic indications").

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

Important information about excipients. The medicinal product contains sucrose. In patients with diabetes or those on a controlled diet, it should be noted that each sachet contains 2.213 g of sucrose. Fosfomycin should not be administered to patients with fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy. The use of single-dose treatment for urinary tract infections in pregnant women is not considered appropriate.

Animal studies have not revealed any direct or indirect adverse effects on pregnancy, embryonal development, fetal development, and/or postnatal development. Available limited data on the safety of fosfomycin use in pregnant women do not indicate an increased risk of congenital malformations or fetal/neonatal toxicity.

During pregnancy, the use of this medicinal product should only be considered if necessary, when the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding. Fosfomycin passes into breast milk even after a single dose. The use of this medicinal product should be discontinued during breastfeeding.

Effects on ability to drive and use machines.

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

Dosage and Administration

The dosage regimen should be determined individually by a physician.

Treatment of acute uncomplicated cystitis. For adult women and girls aged 12 years and older with body weight ≥50 kg, administer 1 sachet (3 g) once daily.

Prophylaxis of infections in adult men undergoing transrectal prostate biopsy. For men with body weight ≥50 kg, administer 1 sachet (3 g) 3 hours before and again 24 hours after the procedure.

Administration method. For oral use.

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

Dissolve the contents of one sachet in a glass of water and drink the solution immediately.

Children.

The drug may be used in 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 hypotension, severe drowsiness, electrolyte disturbances, thrombocytopenia, and hypoprothrombinemia have been reported following parenteral administration of fosfomycin.

Treatment: Symptomatic and supportive therapy. In case of overdose, the patient should be monitored (particularly electrolyte levels in plasma/serum). The patient should be advised to drink plenty of fluids to increase diuresis. Fosfomycin is effectively eliminated from the body by hemodialysis, with a mean half-life of approximately 4 hours.

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 undesirable adverse reactions that have been reported in clinical trials or are known from post-marketing experience.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data). Within each frequency category, reactions are listed in order of decreasing severity.

Reporting of suspected adverse reactions

Reporting of adverse reactions following the registration of a medicinal product is of great importance. It enables ongoing monitoring of the benefit/risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use after the expiry date.

Storage conditions.

Keep out of the reach of children.

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

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA"

Manufacturer's address and place of business.

1, Gordienkivska Street, Kharkiv, Kharkiv region, 61010, Ukraine