Cystaphocin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYSTAPHOCIN (CYSTAPHOCIN)

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. After dissolution, a characteristic citrus aroma is perceived.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other antimicrobial agents. Fosfomycin.

ATC code J01X X01.

Pharmacological properties.

Cystaphocin 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 in peptidoglycan synthesis.

Pharmacodynamics.

Cystaphocin 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 steps in bacterial cell wall synthesis. Fosfomycin may also reduce bacterial adhesion to the urothelial mucosal epithelium, which may be a provoking 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 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.

A large proportion of multidrug-resistant E. coli and other extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae remain susceptible to fosfomycin. Similarly, most strains of methicillin-resistant Staphylococcus aureus (MRSA) 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 causing urinary tract infections, as well as penicillinase-producing strains.

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

In addition, Cystafocin 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. 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 (<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.

Elimination

The plasma elimination half-life 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.

Treatment of acute uncomplicated cystitis in women and girls aged 12 years and older.

Prophylaxis of infections in adult men undergoing transrectal prostate biopsy.

Official recommendations on the 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), 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 enhance gastrointestinal (GI) tract motility reduces absorption of Cystaphocin, leading to decreased serum and urinary concentrations of fosfomycin.

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). Numerous cases of increased antagonistic effect of vitamin K antagonists have been reported 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 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 adults.

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

Clostridioides difficile-associated diarrhea. Cases of Clostridioides difficile-associated colitis 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, the medicinal product should not be used in this age group (see section "Dosage and administration").

Persistent infections. Male patients. In case of persistent infections, thorough examination and reassessment of 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 as complicated urinary tract infections, for which this medicinal product is not indicated (see section "Indications").

Renal impairment. The concentration of fosfomycin in urine remains therapeutically effective for 48 hours if creatinine clearance is above 10 ml/min.

Important information about excipients. The medicinal product contains sucrose. If the patient has diabetes or is on a special diet, it should be noted that each sachet contains 2.213 g of sucrose. Fosfomycin 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, embryonic development, fetal development, and/or postnatal development.

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 clearly needed, when the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding

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

Effect on ability to drive and use machines.

Cystafocin 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 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. For oral use.

For the treatment of acute uncomplicated cystitis in women and girls aged 12 years and older, the dose 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.

The contents of the sachet should be dissolved in one glass of water and the prepared solution should be consumed immediately.

Children

The use in girls aged 12 years and older is indicated 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. It is recommended to increase fluid intake to enhance diuresis.

Adverse reactions

The most common adverse reactions associated with a single dose of fosfomycin trometamol are gastrointestinal disorders, 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 category, adverse reactions are listed in order of decreasing severity.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization 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, are encouraged to 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. 3 years.

Do not use after the expiry date.

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

Keep out of reach and sight of children.

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

Prescription status. Prescription only.

Manufacturer. JSC "Chemical and Pharmaceutical Plant "Chervona Zirka".

Manufacturer's address and location of its operations.

1 Gordienkovska Street, Kharkiv, Kharkiv Oblast, 61010, Ukraine.