PHOSPHOMED

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

Composition:

Active substance: fosfomycin;

1 sachet contains fosfomycin (in the form of trometamol salt) 3 g;

Excipients: sucrose, colloidal anhydrous silicon dioxide, orange essence, mandarin essence, sodium saccharin.

Pharmaceutical form. Granules for oral solution.

Main physico-chemical properties: homogeneous granular powder, white or almost white, with an orange-mandarin odor.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Other antibacterial agents. Fosfomycin. ATC code J01X X01.

Pharmacological properties.

Pharmacodynamics.

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.

Fosfomycin [mono (2-amino-2-hydroxymethyl-1,3-propanediol) (2R-cis)-(3-methyloxiranyl) phosphonate] is an antibiotic derived from phosphonic acid and is used for the treatment of urinary tract infections.

Fosfomycin acts at the first stage of bacterial cell wall synthesis.

The structure of fosfomycin is similar 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 in 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 causing urinary tract infections.

Only a few bacterial species may develop resistance. The resistance rate of E. coli responsible for uncomplicated urinary tract infections is extremely low.

A large proportion of multidrug-resistant E. coli and other extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae remain susceptible to fosfomycin. Similarly, 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 due to the unique chemical structure of fosfomycin and its distinct mechanism of action compared to other antibiotics.

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, susceptibility has been observed against Enterobacter spp., Klebsiella spp., Enterococci, Proteus mirabilis, Staph. aureus, and Staph. saprophyticus.

In addition, fosfomycin reduces bacterial adhesion to the urothelial mucosa, which may be a contributing factor in the development of recurrent urinary tract infections.

Pharmacokinetics.

Absorption.

After oral administration, approximately 50% of fosfomycin is rapidly absorbed. Following a dose of 50 mg/kg body weight, the time to reach maximum plasma concentration (t_max) is 2–2.5 hours, and the maximum plasma concentration (C_max) ranges from 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.

Elimination.

The elimination half-life (t_1/2) from plasma is approximately 4 hours. After a single 3 g dose, 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. Approximately 40–50% of the administered dose is excreted unchanged in urine within the first 48 hours.

Pharmacokinetics in special patient populations.

In patients with renal impairment, elimination of fosfomycin is slowed in proportion to the degree of functional impairment, and t_1/2 is prolonged (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 active substance or to any of the excipients of the medicinal product.
• Use in patients with severe renal impairment (creatinine clearance < 10 ml/min).
• Use in patients undergoing hemodialysis.
• Children under 12 years of age.

Interaction with other medicinal products and other forms of interaction.

When administered concomitantly with metoclopramide and other agents that enhance gastrointestinal motility, absorption of fosfomycin is reduced, leading to decreased plasma and urinary levels of fosfomycin.

Fosfomycin levels in plasma and urine are also reduced when fosfomycin is taken with food. Therefore, it is recommended to administer the medicinal product on an empty stomach or 2–3 hours after eating or taking other medications.

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 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 use of fosfomycin. However, certain classes of antibiotics are more frequently associated with INR fluctuations, including: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Interaction studies have been conducted only in adults.

Special precautions for use

There is insufficient evidence of efficacy of fosfomycin in children, as the 3 g dose is not intended for children under 12 years of age; therefore, the medicinal product should not be used in this age group.

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, which may be life-threatening, may occur during treatment with fosfomycin (see section "Adverse reactions"). If such reactions occur, administration of the medicinal product must be discontinued immediately and appropriate therapy initiated. The medicinal product must never be re-administered.

Antibiotic use, including fosfomycin, may lead to the development of antibiotic-associated diarrhea. The severity may range from mild diarrhea to fatal colitis. The onset of severe, persistent and/or bloody diarrhea during or after (including several weeks after) completion of antibiotic therapy may be a symptom of Clostridium difficile-associated diarrhea (CDAD). Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after treatment with fosfomycin. If CDAD is suspected or confirmed, appropriate therapy should be initiated immediately. In such cases, peristalsis-inhibiting agents are contraindicated.

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

The medicinal product contains sucrose. Patients with diabetes mellitus and those on a controlled diet should be aware that each sachet contains 2.173 g of sucrose. This medicinal product should not be used by patients with fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy.

Single-dose administration for the treatment of 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, 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 medicinal product may be used during pregnancy only if clearly 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 medicinal product should be discontinued during breastfeeding.

Fertility.

Reproductive toxicity was not observed in animal studies. There are no data available on the effect of fosfomycin on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Dizziness may occur during treatment with this medicinal product, which may impair the ability to drive or operate machinery.

Method of Administration and Dosage.

The medicinal product is intended for oral administration. Dissolve the contents of the sachet in a glass of water and take immediately. It should be taken on an empty stomach, preferably before bedtime, after emptying the urinary bladder.

Concomitant food intake delays the absorption of fosfomycin. Therefore, it is advisable to administer the medicinal product on an empty stomach or 2–3 hours after a meal.

The medicinal product in this dosage (3 g) should be used as indicated in patients with a body weight of 50 kg or more.

Treatment.

Women and girls aged 12 years and older with a body weight of at least 50 kg should take one sachet (3 g) as a single dose.

Prophylaxis.

For prevention of infection in men with a body weight of at least 50 kg undergoing prostate biopsy, one sachet (3 g) should be administered 3 hours before and 24 hours after the procedure.

Children.

The medicinal product is 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.

Possible 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.

In case of overdose, symptomatic and supportive therapy should be administered. Increased fluid intake is recommended to enhance diuresis.

Adverse reactions.

The most common adverse reactions associated with a single dose of fosfomycin are gastrointestinal disturbances, primarily diarrhea. These manifestations are usually transient and resolve spontaneously.

The frequency of adverse effects is defined as follows: very common (> 1/10); common (> 1/100 - <1/10); uncommon (> 1/1000 - <1/100); rare (> 1/10000 - <1/1000); very rare (<1/100000); not known (cannot be estimated from available data).

Within each frequency group, 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 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.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

8 g of granules (3 g of active substance) in sachets; 1 or 2 sachets per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address and place of business.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.