Fosfocin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOSPHOCIN

Composition:

Active substance: fosfomycin;

1 sachet contains: fosfomycin (as fosfomycin trometamol) - 3 g;

Excipients: sucrose, sodium saccharin, mandarin and orange flavorings.

Pharmaceutical form. Granules for oral solution.

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

Pharmacotherapeutic group. Antimicrobial agents for systemic use.
Other antimicrobial agents. Fosfomycin. ATC code J01XX01.

Pharmacological properties.

Fosfocin 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.

Fosfocin 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 mucosal epithelium, which may be a triggering 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 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 β-lactamase (ESBL)-producing Enterobacteriaceae are susceptible to fosfomycin. Likewise, 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 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, fosfomycin reduces bacterial adhesion to the urothelial epithelium, 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. 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, concentrations in urine of 1800–3000 μg/mL are achieved within 2–4 hours. Therapeutically effective concentrations (200–300 μg/mL) may 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 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 lower urinary tract infections caused by microorganisms sensitive to fosfomycin in males and in girls aged 12 years and older, and adult women. Prophylaxis during diagnostic procedures and surgical interventions in adult patients.

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 forms of interaction.

Concomitant use with metoclopramide and other medicinal products that enhance gastrointestinal motility reduces the absorption of Fosfocin, leading to decreased concentrations in blood serum and urine.

Administration of the drug during meals reduces plasma and urinary levels of fosfomycin; therefore, Fosfocin should be taken on an empty stomach or 2–3 hours after eating or after taking other medicinal products.

Specific issues regarding fluctuations in INR (International Normalized Ratio). Numerous cases of increased antagonistic activity of vitamin K antagonists have been reported in patients taking antibiotics. Risk factors include: severe infections or inflammation, advanced age, and poor general health. In such cases, it is difficult to determine whether the change in INR is related to the infectious disease or caused by drug intake. However, certain classes of antibiotics are more frequently associated with INR fluctuations, particularly: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Interaction studies were conducted only in adults.

Special precautions for use.

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

Administration of phosphomycin may lead to hypersensitivity reactions, including anaphylaxis and anaphylactic shock, which may be life-threatening (see section "Adverse reactions"). If such reactions occur, phosphomycin should be discontinued immediately, and re-administration of phosphomycin to such patients is contraindicated. Appropriate therapeutic measures should be initiated.

Use of antibiotics, including trometamol phosphomycin, may lead to antibiotic-associated diarrhea. The severity may range from mild diarrhea to colitis with fatal outcome. Development of severe, persistent and/or bloody diarrhea during or after (including several weeks after) completion of antibiotic therapy may indicate Clostridium difficile-associated diarrhea (CDAD). This diagnosis should therefore be considered in patients who develop severe diarrhea during or after treatment with trometamol phosphomycin. If CDAD is suspected or confirmed, appropriate treatment should be initiated immediately. In such cases, drugs that inhibit peristalsis are contraindicated.

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

Fosfocin contains sucrose. Patients with diabetes mellitus and those on a controlled diet should be aware that one sachet of Fosfocin contains 2.213 g of sucrose. Fosfocin 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 administration for the treatment of urinary tract infections in pregnant women is not considered appropriate.

Animal studies have not revealed any direct or indirect toxic effects on pregnancy, embryonal development, fetal development, and/or postnatal development.

There are only limited data on the safety of phosphomycin use in pregnant women. These data do not indicate the development of congenital malformations or fetal/neonatal toxicity of phosphomycin.

During pregnancy, the use of the medicinal product is possible only if necessary, when the expected benefit of therapy for the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding

Fosfocin passes into breast milk even after a single dose; therefore, its use should be discontinued during breastfeeding.

Ability to affect reaction speed when driving or operating machinery. Fosfocin may cause dizziness, which may affect the ability to drive or operate machinery.

Method of Administration and Dosage

Fosfocin should be taken orally on an empty stomach, preferably at bedtime, after emptying the urinary bladder. The contents of 1 sachet should be dissolved in a glass of water and taken immediately.

Concomitant food intake slows down the absorption of fosfomycin. Therefore, it is recommended to take the drug on an empty stomach or 2–3 hours after eating.

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

Treatment
Adults and adolescents with body weight of 50 kg or more should take 1 sachet (3 g) of Fosfocin once daily.
Prophylaxis

Adults with body weight of 50 kg or more should take 1 sachet (3 g) of Fosfocin 3 hours before and 24 hours after the procedure.

Children. The use for treatment of acute uncomplicated lower urinary tract infections in girls aged 12 years and older is possible.

There are insufficient data on the use of the drug for therapeutic purposes in boys aged 12 years and older, as well as insufficient data on the use of the drug for prophylactic purposes in both boys and girls.

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.

Treatment: symptomatic and supportive therapy. It is recommended to drink plenty of fluids to increase diuresis.

Adverse Reactions

The most common adverse reactions following a single dose of fosfomycin trometamol are gastrointestinal disorders, primarily diarrhea. These manifestations 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 (≥ 1/1,000 to <1/100);
rare (≥ 1/10,000 to <1/1,000);
very rare (< 1/10,000);
not known (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in decreasing order of severity.

Reporting of Adverse Reactions

It is important to report adverse reactions following the registration of medicinal products. This enables continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are obliged to report any adverse reactions through the national reporting system.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

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

Packaging. 3 g granules for oral solution in sachets, 2 sachets in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

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

Marketing Authorization Holder.

Pharmaceutical company «Vocate S.A.».

Address of the Marketing Authorization Holder.

16674 Glyfada, Gounari str., 150 Athens, Greece.