Phosphoseptic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Fosfoseptic (Fosfoseptic)

Composition:

Active substance: fosfomycin;

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

Excipients: sucrose, anhydrous citric acid, anhydrous magnesium citrate, sodium saccharin (E 954), natural orange flavor, natural tangerine flavor.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: a mixture of powder and granules of almost white color with a citrus odor.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other antimicrobials. Fosfomycin. ATC code J01X X01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Fosfomycin exerts a bactericidal effect on proliferating pathogenic microorganisms by inhibiting the enzymatic synthesis of the bacterial cell wall. Fosfomycin inhibits the first step of intracellular bacterial cell wall synthesis by blocking peptidoglycan synthesis.

Fosfomycin is actively transported into the bacterial cell via two different transport systems (sn-glycerol-3-phosphate and hexose-6-phosphate transport systems).

Pharmacokinetic/pharmacodynamic relationship

Limited data suggest that fosfomycin most likely exhibits time-dependent activity.

Resistance mechanism

The primary resistance mechanism is chromosomal mutation causing alterations in bacterial fosfomycin transport systems. Additional resistance mechanisms mediated by plasmids or transposons lead to enzymatic inactivation of fosfomycin either by conjugation of the molecule with glutathione or, respectively, by cleavage of the carbon-phosphorus bond in the fosfomycin molecule.

Cross-resistance

Cross-resistance between fosfomycin and other classes of antibiotics is not known.

Breakpoints for susceptibility testing

The susceptibility breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are provided in Table 1 below.

Table 1

EUCAST (version 10) susceptibility breakpoints

Acquired resistance prevalence

The prevalence of acquired resistance in individual species may vary depending on geographical location and over time. Therefore, local information on resistance patterns is necessary, primarily to ensure appropriate treatment of severe infections.

The information provided below is based on data from monitoring programs and studies. It includes data on microorganisms meeting approved indicators.

Commonly susceptible species

Aerobic gram-negative microorganisms

Escherichia coli.

Species for which acquired resistance may be a concern

Aerobic gram-positive microorganisms

Enterococcus faecalis.

Aerobic gram-negative microorganisms

Klebsiella pneumoniae,

Proteus mirabilis.

Species with intrinsic resistance

Aerobic gram-positive microorganisms

Staphylococcus saprophyticus.

Pharmacokinetics.

Absorption

After oral administration of a single dose, the absolute bioavailability of fosfomycin trometamol is approximately 33–53%. The rate and extent of absorption are reduced by food, but the total amount of active substance excreted in urine over time remains unchanged. The average concentration of fosfomycin in urine remains above the threshold minimum inhibitory concentration (MIC) of 128 µg/mL for at least 24 hours after an oral 3 g dose taken either fasting or after food, although the time to reach peak concentration in urine is delayed by 4 hours. Fosfomycin trometamol undergoes enterohepatic recirculation.

Distribution

Fosfomycin is not metabolized. Fosfomycin distributes into tissues, including kidneys and the bladder wall. Fosfomycin does not bind to plasma proteins and crosses the placental barrier.

Elimination

Fosfomycin is excreted unchanged by the kidneys via glomerular filtration (40–50% of the dose is excreted in urine) with a half-life of approximately 4 hours after oral administration, and to a lesser extent in feces (18–28% of the dose). Although food slows the absorption of the active substance, the total amount of active substance excreted in urine remains unchanged.

Special patient groups

In patients with impaired renal function, elimination half-life increases proportionally to the degree of renal impairment. Fosfomycin concentration in urine in patients with impaired renal function remains effective for up to 48 hours after administration of the standard dose, provided creatinine clearance exceeds 10 mL/min.

In elderly patients, fosfomycin clearance is reduced in accordance with age-related decline in renal function.

Safety pharmacology – preclinical data

Preclinical data from standard safety pharmacology, repeated-dose toxicity, genotoxicity, and reproductive toxicity studies revealed no special hazard for humans.

Data on the carcinogenicity of fosfomycin are not available.

Clinical characteristics.

Indications.

Treatment of acute uncomplicated cystitis in women and girls.

Perioperative antibiotic prophylaxis in transrectal biopsy of the prostate gland in adult men.

Attention should be paid to the official guidelines on the appropriate use of antibacterial agents.

Contraindications.

Hypersensitivity to the active substance, fosfomycin trometamol, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other types of interactions.

Metoclopramide

Concomitant administration with metoclopramide results in reduced serum and urinary concentrations of fosfomycin and should therefore be avoided.

Other drugs that enhance gastrointestinal motility may produce similar effects.

Food effects

Food may delay the absorption of fosfomycin, resulting in a slight reduction in the maximum plasma concentration and urinary concentration. Therefore, it is advisable to take the medicinal product on an empty stomach or approximately 2–3 hours after a meal.

Specific problems related to changes in international normalized ratio (INR) values

Numerous cases of increased activity of oral anticoagulants have been reported in patients taking antibiotics. Risk factors include severe infections or inflammation and deterioration of general health status. Under such circumstances, it is difficult to determine whether the change in INR is related to the infectious disease or to its treatment. However, certain classes of antibiotics are more frequently implicated, particularly fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Hypersensitivity reactions

Severe, 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 should be discontinued immediately and appropriate emergency measures initiated.

Clostridioides difficile-associated diarrhea

Cases of colitis and pseudomembranous colitis caused by Clostridioides difficile, with severity ranging from moderate to life-threatening, have been reported during treatment with fosfomycin (see section "Side effects"). This diagnosis should therefore be considered in patients who develop diarrhea during or after treatment with fosfomycin. Discontinuation of fosfomycin and initiation of specific therapy for Clostridioides difficile infection should be considered. Antiperistaltic medicinal products should not be prescribed.

Children

The safety and efficacy of the medicinal product Fosphosetik in children under 12 years of age have not been established; therefore, it 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 diagnosis are recommended, as these are often associated with complicated urinary tract infections or 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 "Indications").

Excipients

Fosphosetik contains sucrose. It is not recommended for use in patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy

Only limited data on the safety of fosfomycin treatment during the first trimester of pregnancy are available (n = 152). To date, these data have not shown any safety signal regarding teratogenicity.

Fosfomycin crosses the placenta.

Animal studies have not revealed any direct or indirect harmful effects related to reproductive toxicity (see section "Preclinical safety data").

Fosphosetik should be used during pregnancy only if clearly necessary.

Breastfeeding

Fosfomycin is excreted in human breast milk in small amounts. A single oral dose of fosfomycin may be administered during breastfeeding if necessary.

Fertility

There are no data available on fertility in humans. Oral administration of fosfomycin at doses up to 1000 mg/kg/day in male and female rats did not affect fertility (see section "Side effects").

Ability to influence reaction speed when driving or operating machinery.

Specific studies have not been conducted; however, patients should be informed that dizziness has been reported. This may affect the ability of some patients to drive vehicles or operate machinery.

Method of Administration and Dosage

Dosage

Acute uncomplicated cystitis in women and girls (aged > 12 years): a single 3 g dose of fosfomycin.

Perioperative antibiotic prophylaxis in transrectal prostate biopsy: 3 g of fosfomycin 3 hours before the procedure and 3 g of fosfomycin 24 hours after the procedure.

Renal Function Impairment

The use of Fosphoseptic is not recommended in patients with severe renal impairment (creatinine clearance < 10 mL/min; see section "Pharmacokinetics").

Method of Administration

For oral use.

In acute uncomplicated cystitis in women and girls, the medicinal product should be taken on an empty stomach (2–3 hours before or 2–3 hours after a meal), preferably at bedtime, and after emptying the bladder.

The dose should be dissolved in a glass of water and the solution should be consumed immediately after preparation.

Children

The safety and efficacy of Fosphoseptic in children under 12 years of age have not been established.

Overdose

Experience with fosfomycin overdose following oral administration is limited. With parenteral administration of fosfomycin, isolated cases of arterial hypotension, drowsiness, electrolyte imbalance, thrombocytopenia, and hypoprothrombinemia have been observed.

In case of overdose, the patient should be monitored (particularly for plasma/serum electrolyte levels), and symptomatic and supportive treatment should be administered. Rehydration is recommended to promote the elimination of the active substance through urine. Fosfomycin is effectively removed from the body by hemodialysis, with a mean half-life of elimination of approximately 4 hours.

Adverse reactions.

Summary of safety profile

The most common adverse reactions following a single dose of fosfomycin trometamol occur in the gastrointestinal tract and are predominantly manifested as diarrhea. These reactions are transient and resolve spontaneously.

List of adverse reactions

Table 2 below presents a list of adverse reactions reported during clinical trials and the post-marketing period with the use of fosfomycin trometamol.

Adverse reactions are listed by system organ class and frequency, using the following categories:

Very common (≥ 1/10).

Common (≥ 1/100 to < 1/10).

Uncommon (≥ 1/1,000 to < 1/100).

Rare (≥ 1/10,000 to < 1/1,000).

Very rare (< 1/10,000).

Frequency not known (cannot be estimated from the available data).

Table 2

Adverse reactions

Reporting suspected adverse reactions

Reporting adverse reactions following the registration of a medicinal product is of great importance. It enables 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 via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 8.0 g of granules for oral solution in sachets; 1 or 2 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Adipharm EAD / Adipharm EAD.

Manufacturer's address and place of business.

130 Simeonovsko shose Blvd., Sofia, 1700, Bulgaria / 130 Simeonovsko shose Blvd., Sofia, 1700, Bulgaria.