Fosfomycin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOSPHOMYCIN (FOSFOMYCIN)

Composition:

active substance: fosfomycin;

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

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

Pharmaceutical form. Granules for oral solution.

Basic physico-chemical properties: white granular powder with a characteristic odor of mandarin flavoring.

Pharmacotherapeutic group.

Antimicrobials 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 steps 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 uridine diphosphate-N-acetylglucosamine with phosphoenolpyruvate, one of the initial stages of bacterial cell wall synthesis. Fosfomycin may also reduce bacterial adhesion to the urothelial mucosa, which may be a triggering factor for 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 disc-diffusion method using fosfomycin trometamol 200 μg discs. 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 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 are susceptible to fosfomycin. Likewise, the majority of methicillin-resistant Staphylococcus aureus strains 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 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 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.

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) persist 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 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.

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 any of the excipients, 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 absorption of fosfomycin, leading to decreased concentrations of the drug in serum and urine.

Administration of the medicinal product with food reduces plasma and urinary levels of fosfomycin. 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 inflammation, 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 or caused by the intake of the medicinal product. 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 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, treatment with fosfomycin must be discontinued immediately and appropriate emergency measures should be taken.

Clostridioides difficile-associated diarrhea.

Cases of colitis associated with Clostridioides difficile and pseudomembranous colitis have been reported during treatment with fosfomycin, with severity ranging from mild to life-threatening (see section "Special precautions for use"). Therefore, this diagnosis should be considered in patients who develop diarrhea during or after treatment with fosfomycin. 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, this medicinal product should not be used in this age group (see section "Dosage and administration").

Persistent infections and male patients.

In cases of persistent infections, careful examination and re-evaluation of the 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 as complicated urinary tract infections, for which this medicinal product is not indicated (see section "Indications").

Renal impairment.

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

Important information about excipients.

The medicinal product contains sucrose. Diabetic patients and those requiring dietary restrictions should be aware that each sachet contains 2.213 g of suc游戏副本

Method of Administration and Dosage

The drug is taken orally on an empty stomach, preferably at bedtime after emptying the urinary bladder. The contents of the sachet should be dissolved in ½ glass of water. The dosage regimen is determined individually by a physician.

Treatment of acute uncomplicated cystitis.

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) once daily.

Prophylaxis of infections in adult men undergoing transrectal prostate biopsy.

For men with body weight of 50 kg or more, administer 1 sachet (3 g) 3 hours before and 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 urinary bladder.

Dissolve the contents of the sachet in 1 glass of water and drink the prepared solution 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. In case of overdose, the patient should be monitored (particularly plasma/serum electrolyte levels). It is recommended to increase fluid intake to enhance 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 adverse reactions observed in clinical trials or reported 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 (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse 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 allows continuous monitoring of the benefit-risk balance of the 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 through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

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 coated foil. Packaged in cardboard boxes containing 1, 2, 3, 4, or 10 sachets.

Prescription status.

Prescription only.

Manufacturer.

ASTRAFARM LLC, Ukraine.

Manufacturer's address and location of its business activity.

6, Kyivska Street, city of Vyshneve, Bucha district, Kyiv region, 08132, Ukraine.