PHOSPHORAL

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

Composition:

Active substance: fosfomycin;

1 sachet contains 5.631 g of fosfomycin trometamol, equivalent to 3 g of fosfomycin;

Excipients: mandarin flavor, orange flavor, saccharin, sucrose.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white granular powder with a characteristic fruity odor (orange-mandarin).

Pharmacotherapeutic group. Antimicrobial agents for systemic use.

Other antimicrobial agents. ATC code J01X X01.

Pharmacological properties.

Fosforal 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.
Fosforal 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 affects 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 uridinediphosphate-N-acetylglucosamine with phosphoenolpyruvate—one of the earliest stages in bacterial cell wall synthesis. Fosfomycin may also reduce bacterial adhesion to the urothelial mucosa, which could be a triggering factor in the development of recurrent infections.

The table below presents data on the in vitro activity 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.

Most multidrug-resistant E. coli and other extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae remain susceptible to fosfomycin. Likewise, the majority of methicillin-resistant Staphylococcus aureus (MRSA) strains 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, susceptibility has been observed in Enterobacter spp., Klebsiella spp., Enterococci, Proteus mirabilis, Staph. aureus, and Staph. saprophyticus.

In addition, Monural reduces bacterial adhesion to the urothelial mucosa, which may be a triggering factor for recurrent urinary tract 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 (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 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 administered 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 types of interactions.

Concomitant administration with metoclopramide and other drugs that enhance gastrointestinal motility reduces absorption of Fosforal, resulting in decreased serum and urinary concentrations of Fosforal.

Administration of the drug 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 medications.

Specific issues related to 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 associated with the infectious disease itself or caused by the 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 have been conducted only in adults.

Special precautions for use.

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

Use of fosfomycin may lead to development of hypersensitivity reactions, including anaphylaxis and anaphylactic shock, which may be life-threatening (see section "Adverse reactions").

If such reactions occur, fosfomycin should be discontinued immediately, and re-administration of fosfomycin to these patients is contraindicated. Appropriate therapeutic measures should be initiated.

Use of antibiotics, including fosfomycin trometamol, may lead to development of antibiotic-associated diarrhea. The severity may range from mild diarrhea to fatal colitis. Development of severe, persistent and/or bloody diarrhea during or after (including several weeks after) completion of antibiotic therapy may indicate diarrhea caused by Clostridium difficile (CDAD). Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after taking fosfomycin trometamol. 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 fosfomycin in urine remains therapeutically effective for 48 hours if creatinine clearance is above 10 ml/min.

Phosphoral contains sucrose. Patients with diabetes mellitus or those on a special diet should be aware that each sachet of Phosphoral contains 2.213 g of sucrose. Phosphoral should not be used in patients with hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy

The use of single doses 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, 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.

During pregnancy, the use of the medicinal product may be considered only if clearly necessary, when the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding

Phosphoral is excreted in breast milk even after a single dose. Therefore, use of the drug should be discontinued during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Phosphoral may cause dizziness, which may affect the ability to drive or operate machinery.

Method of Administration and Dosage.

Phosphoral should be taken orally on an empty stomach, preferably before bedtime, 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. Concurrent food intake delays the absorption of fosfomycin. Therefore, it is advisable to administer the drug on an empty stomach or 2–3 hours after a meal.

The medicinal product in this dosage (3 g) is indicated for patients with a body weight of 50 kg or more.

Treatment

Adults and adolescents with a body weight of ≥50 kg: one 3 g sachet of Phosphoral once daily.

Prophylaxis

Adults with a body weight of ≥50 kg: one 3 g sachet of Phosphoral 3 hours before and 24 hours after the procedure.

Children.

Phosphoral may be used for the treatment of acute uncomplicated lower urinary tract infections in girls aged 12 years and older.

There is 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.

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 disturbances, primarily diarrhea. These events 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 the available data).

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

Table 1

Shelf life.
3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C.

Packaging.
8 g per sachet; 1 sachet in a cardboard pack.

Prescription status.
Prescription only.

Manufacturer.
Labiana Farmacéutica, S.L.U.

Manufacturer's name and address.
C/Casanova, 27-31, Cubelles de Llobregat, 08757, Barcelona, Spain.