Fosfokok

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOSPHOCOC (FOSFOCOC)

Composition:

Active substance: fosfomycin;

1 sachet contains 5.631 g of fosfomycin trometamol, equivalent to 3 g of fosfomycin;
Excipients: sucrose, sodium saccharin, mandarin flavor, orange flavor.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white or almost white granules, free from lumps or particles.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other antimicrobials. Fosfomycin. 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 minimum 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 bacterial species 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 beta-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 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 contributing factor in the development of 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 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 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 the 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 types of interactions.

Concomitant administration with metoclopramide and other medicinal products that enhance gastrointestinal motility reduces absorption of fosfomycin, leading to decreased drug concentrations in plasma and urine.

Administration of the medicinal product during meals 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 activity 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 may be difficult to determine whether changes in INR are related to the infectious disease itself or caused by the medicinal product. However, certain classes of antibiotics are 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.

Severe and sometimes fatal hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during treatment with fosfomycin (see sections "Contraindications" and "Side effects"). If such reactions occur, fosfomycin therapy must be discontinued immediately and appropriate emergency measures should be initiated.

Clostridioides difficile-associated diarrhea.

Cases of colitis associated with Clostridioides difficile 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 receiving fosfomycin. Discontinuation of fosfomycin therapy and initiation of specific treatment for Clostridioides difficile should be considered. Antiperistaltic medicinal products should not be used.

Paediatric 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 reassessment of the diagnosis are recommended, as these are often associated with complicated urinary tract infections or the presence 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 "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 on a controlled diet should be aware that each sachet contains 2.213 g of sucrose. FOSPHOCOK should not be administered to patients with hereditary 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 shown any direct or indirect adverse effects on pregnancy, embryonal development, fetal development, or postnatal development. However, there are only limited data on the safety of fosfomycin use in pregnant women. These data do not indicate an increased risk of congenital malformations or fetal/neonatal toxicity associated with fosfomycin.

The use of this medicinal product during pregnancy may be considered if necessary, when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding.

Fosfomycin passes into breast milk even after a single dose. Therefore, use of the 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

Treatment of acute uncomplicated cystitis.

For adult women and girls aged 12 years and older with body weight of 50 kg or more, administer 1 sachet of the medicinal product (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 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 one glass of water and immediately drink the prepared solution.

Children.

The drug may be administered to girls aged 12 years and older for 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, 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 an average elimination half-life of approximately 4 hours.

Adverse reactions.

The most common adverse reactions associated with single-dose administration of fosfomycin trometamol are gastrointestinal disorders, primarily diarrhea. These events are usually transient and resolve spontaneously.

The table below lists adverse reactions identified from clinical trials or reported during 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), 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 adverse reactions after marketing authorization of a medicinal product is of great importance. It enables continuous 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 through the Automated Pharmacovigilance Information System 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 30 °C. Keep out of the reach and sight of children.

Packaging.

8 g of granules in sachets; 1 or 2 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Labiana Farmacéuticas, S.L.U. / Labiana Pharmaceuticals, S.L.U.

Manufacturer's address and place of business.

C/Casanova, 27-31, Corbera de Llobregat, Barcelona, 08757, Spain.