Exelfos

White granules with fruit flavor (orange-mandarin).
Each sachet contains 3 g of Fosfomycin (as Fosfomycin trometamol 5.631 g).
Excipient(s) with known effect: Each single-dose sachet contains 2.2 g of sucrose, 7.5 mg of glucose.
Excipients/Inactive Ingredients: Sucrose, Sodium saccharin, Mandarin flavour (contains glucose from maize maltodextrin and sodium), Orange flavour (contains glucose from maize maltodextrin and sodium).

Pharmacotherapeutic group: Antibacterial for systemic use-other antibacterials. ATC code: J01XX01.
Pharmacology: Pharmacodynamics: Mechanism of action: Fosfomycin exerts a bactericidal effect on proliferating pathogens by preventing the enzymatic synthesis of the bacterial cell wall. Fosfomycin inhibits the first stage of intracellular bacterial cell wall synthesis by blocking peptidoglycan synthesis.
Fosfomycin is actively transported into the bacterial cell via two different transport systems (the sn-glycerol-3-phosphate and hexose-6 transport systems).
Pharmacokinetic/pharmacodynamic relationship: Limited data indicate that Fosfomycin most likely acts in a time-dependent manner.
Mechanism of resistance: Main mechanism of resistance is a chromosomal mutation causing an alteration of the bacterial Fosfomycin transport systems. Further resistance mechanisms, which are plasmid- or transposon-borne, cause enzymatic inactivation of Fosfomycin by binding the molecule to glutathione or by cleavage of the carbon-phosphorus-bond in the Fosfomycin molecule, respectively.
Cross-resistance: Cross-resistance between Fosfomycin and other antibiotic classes is not known.
Susceptibility testing breakpoints: The susceptibility breakpoints established by the European Committee on Antimicrobial Susceptibility Testing are as follows (EUCAST breakpoint table version 11): See Table 1.

Click on icon to see table/diagram/image

Prevalence of acquired resistance: The prevalence of acquired resistance of individual species may vary geographically and over time. Local information about the resistance situation is therefore necessary, particularly in order to ensure appropriate treatment of severe infections.
The following text is based on data from surveillance programs and studies. It comprises organisms relevant for the approved indications: Commonly susceptible species: Aerobic Gram-negative microorganisms: Escherichia coli.
Species in which acquired resistance may be a problem: Aerobic Gram-positive microorganisms: Enterococcus faecalis.
Aerobic Gram-negative microorganisms: Klebsiella pneumonia, Proteus mirabilis.
Inherently resistant species: Aerobic Gram-positive microorganisms: Staphylococcus saprophyticus.
Pharmacokinetics: Absorption: After single-dose oral administration, Fosfomycin trometamol has an absolute bioavailability of about 33-53%. Rate and extent of absorption are reduced by food, but the total amount of active substance excreted in the urine over time is the same. Mean urinary Fosfomycin concentrations are maintained above an MIC threshold of 128 μg/mL for at least 24 h post 3 g oral dose in either the fasting or fed state, but the time to reach maximal concentrations in urine are delayed by 4 h. Fosfomycin trometamol undergoes enterohepatic recirculation.
Distribution: Fosfomycin does not appear to be metabolised. Fosfomycin is distributed to tissues including the kidneys and bladder wall. Fosfomycin is not bound to plasma proteins and crosses the placental barrier.
Elimination: Fosfomycin is excreted unchanged mainly via the kidneys by glomerular filtration (40-50% of the dose is found in the urine) with an elimination half-life of about 4 hours after oral use and to a lesser extent in faeces (18-28% of the dose). Even if food delays drug absorption, the total amount of drug excreted in the urine over time is the same.
Special populations: In patients with impaired renal function, the elimination half-life is increased proportionally to the degree of renal insufficiency. Urinary concentrations of Fosfomycin in patients with impaired renal function remain effective for 48 hours after a usual dose if creatinine clearance is above 10 ml/min.
In order people Fosfomycin clearance is reduced in line with the age related reduction in renal function.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction.
No carcinogenicity data are available for Fosfomycin.

Acute bacterial cystitis, acute episodes in relapsing bacterial cystitis, acute bacterial urethra-vesical syndrome, nonspecific bacterial urethritis which susceptible to the drug etc. Escherichia coli; Significant asymptomatic bacteriuria (in pregnancy).

Posology: Acute, uncomplicated cystitis in women and female adolescents (>12 years of age): 3 g Fosfomycin once.
Perioperative antibiotic prophylaxis for transrectal prostate biopsy: 3 g Fosfomycin 3 hours prior to the procedure and 3 g Fosfomycin 24 hours after the procedure.
Renal impairment: Use of Exelfos is not recommended in patients with renal impairment (creatinine clearance <10 ml/min, see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of Exelfos in children aged below 12 years of age have not been established.
Method of administration: For oral use.
For the indication of acute, uncomplicated cystitis in women and female adolescents it should be taken on an empty stomach (about 2-3 hours before or 2-3 hours after a meal), preferably before bedtime and after emptying the bladder.
The dose should be dissolved into a glass of water and taken immediately after its preparation.

Experience regarding the overdose of oral Fosfomycin is limited. Cases of hypotonia, somnolence, electrolytes disturbances, thrombocytopenia and hypoprothrombinemia have been reported with parenteral use of Fosfomycin.
In the event of overdose, the patient must be monitored (particularly for plasma/serum electrolyte levels), and treatment should be symptomatic and supportive. Rehydration is recommended to promote urinary elimination of the active substance. Fosfomycin is effectively cleared from the body by haemodialysis with a mean elimination half-life of approximately 4 hours.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during Fosfomycin treatment (see Contraindications and Adverse Reactions). If such reactions occur, treatment with Fosfomycin must be discontinued immediately and adequate emergency measures must be initiated.
Clostridioides difficile-associated diarrhea: Clostridioides difficile-associated colitis and pseudo-membranous colitis have been reported with Fosfomycin and may range in severity from mild to life-threatening (see Adverse Reactions). Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or subsequent to the administration of Fosfomycin. Discontinuation of therapy with Fosfomycin and the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Persistent infections and male patients: In case of persistent infections, a thorough examination and a re-evaluation of the diagnosis is recommended as this is often due to complicated urinary tract infections or the prevalence of resistant pathogens (e.g. Staphylococcus saprophyticus, see Pharmacology: Pharmacodynamics under Actions). In general, urinary tract infections in male patients have to be considered as complicated UTIs for which this medicinal product is not indicated (see Indications/Uses).
Excipients: Sucrose: Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not use this medicine.
Effects on ability to drive and use machines: No specific studies have been performed but patients should be informed that dizziness has been reported. This may influence some patients' ability to drive and use the machines (see Adverse Reactions).
Use in Children: The safety and efficacy of Exelfos in children below 12 years of age have not been established. Therefore, this medicine should not be used in this age group (see Dosage & Administration).

Pregnancy: Only limited data on the safety of Fosfomycin treatment during 1st trimester of pregnancy (n=152) are available. These data do not raise any safety signal for teratogenicity so far. Fosfomycin crosses the placenta.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Exelfos should only be used during pregnancy, if clearly necessary.
Breast-feeding: Fosfomycin is excreted in human milk in low quantities. If clearly necessary, a single dose of oral Fosfomycin can be used during breast-feeding.
Fertility: No data in humans are available. In male and female rats oral administration of Fosfomycin up to 1000 mg/kg/d did not impair fertility.

Summary of the safety profile: The most common adverse reactions following the single-dose administration of Fosfomycin trometamol involve the gastrointestinal tract, mainly diarrhea. These events are usually self-limited in duration and resolve spontaneously.
Tabulated list of adverse reactions: The following table displays adverse reactions that have been reported with the use of Fosfomycin trometamol from either clinical-trial or post-marketing experiences.
Undesirable effects are listed by body system and frequency using the following convention: 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 form the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 2.)

Click on icon to see table/diagram/image

Metoclopramide: Concomitant administration of metoclopramide has been shown to lower serum and urinary concentrations of Fosfomycin and should be avoided.
Other medicinal products that increase gastrointestinal motility may produce similar effects.
Food effect: Food may delay the absorption of Fosfomycin, with consequent slight decrease in peak plasma levels and urinary concentrations. It is therefore preferable to take the medicinal product on an empty stomach or about 2-3 hours after meals.
Specific problems concerning the alteration INR: Numerous cases of increased oral anticoagulant activity have been reported in patients receiving antibiotic therapy. Risk factors include severe infection or inflammation, age and poor general health. Under these circumstances, it is difficult to determinate whether the alteration in INR is due to the infectious disease or its treatment. However, certain classes of antibiotics are more often involved and in particular: fluoroquinolones, macrolides, cyclins, cotrimoxazole and certain cephalosporins.
Paediatric population: Interaction studies have only been performed in adults.

Incompatibilities: Not applicable.

Store below 30°C. Protect from humidity.
Shelf life: 3 years.

Other Antibiotics

J01XX01 - fosfomycin ; Belongs to the class of other antibacterials. Used in the systemic treatment of infections.

D