ALEXI 3G GRANULES FOR ORAL SOLUTION - summary of medicine characteristics

Alexi 3g granules for oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single-dose sachet contains 5631 mg fosfomycin trometamol, equivalent to 3 g fosfomycin.

Excipients with known effect: Each single-dose sachet contains 1.923 g of sucrose; see section 4.4.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Granules for oral solution.

White, off-white granules in a single-dose sachet.

4.1 Therapeutic indications

Alexi is indicated for (see section 5.1):

– the treatment of acute, uncomplicated cystitis in women and female adolescents

– perioperative antibiotic prophylaxis for transrectal prostate biopsy in adult men Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

Acute, uncomplicated cystitis

Adult women and adolescent females (>12 years of age): 1 sachet (3 g) once

Perioperative antibiotic prophylaxis for transrectal prostate biopsy:

Adults: One fosfomycin 3 g sachet 3 hours before the procedure and a second dose of 3 g 24 hours after the procedure.

Renal impairment:

Use of Alexi is not recommended in patients with renal impairment (creatinine clearance < 10 ml/min, see section 5.2).

Paediatric population

The safety and efficacy of Alexi in children 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 Alexi 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during fosfomycin treatment (see sections 4.3 and 4.8). If such reactions occur, treatment with fosfomycin must be discontinued immediately and adequate emergency measures must be initiated.

Clostridioides difficile -associated diarrhoea

Clostridioides difficile-associated colitis and pseudo-membranous colitis have been reported with fosfomycin and may range in severity from mild to life-threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea 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.

Paediatric population

The safety and efficacy of Alexi in children below 12 years of age have not been established. Therefore, this medicine should not be used in this age group (see section 4.2).

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 section 5.1). In general, urinary tract infections in male patients have to be considered as complicated UTIs for which this medicinal product is not indicated (see section 4.1).

Excipients

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially ‘sodium-free’.

Sucrose

Alexi 3g granules for oral solution contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Metoclopramide

Concomitant administration of metoclopramide has been shown to lower serum and urinary concentrations of fosfomycin and should be avoided.

Other drugs that increase gastrointestinal motility may produce similar effects.

Paediatric population

Interaction studies have only been performed in adults.

Food Effect

Food may delay the absorption of the active ingredient, with consequent slight decrease in peak plasma levels and urinary concentrations. It is therefore preferable to take the medicine on an empty stomach or about 2 – 3 hours after meals.

Specific problems concerning the alteration in INR

Numerous cases of increased oral anticoagulant activity 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.

4.6 Pregnancy and lactation

Pregnancy

Only limited data on the safety of fosfomycin treatment during the 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 section 5.3).

Alexi 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.

4.7 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 machines.

4.8 Undesirable effects

The most common adverse reactions following the single-dose administration of fosfomycin trometamol involve the gastrointestinal tract, mainly diarrhoea. These events are usually self-limited in duration and resolve spontaneously.

The following table displays ADRs that have been reported with the use of fosfomycin from either clinical-trial or post-marketing experiences.

Adverse reactions are listed below by System Organ Class and Frequency according to the MedDRA frequency convention and System Organ Classification:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials.

ATC code: J01XX01

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 (PK)/pharmaco­dynamic (PD) 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 1.1):

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 table 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

5.2 Pharmacokinetic properties

Absorption

After single-dose oral administration, fosfomycin trometamol has an absolute bioavailability of about 34–53%. 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 jig/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 administration, 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 older people fosfomycin clearance is reduced in line with the age-related reduction in renal function.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Saccharin sodium

Sucrose

Orange flavour consisting of:

maltodextrin,

dextrose monohydrate,

acacia (E414),

butylhydroxyanisole (E320),

Natural orange essential oil,

Natural lemon essential oil

linalol

ethyl butyrate

ethyl hexanoate

isoamyl hexanoate

natural citral 96%

isoamyl acetate

nerol

6.2 Incompati­bilities

Not applicable.

6.3 Shelf life

Unopened sachets: 3 years

After reconstitution: The reconstituted solution should be used immediately.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Paper/LDPE/Alu/LDPE sachet

1 sachet of 8 g (of which 3g is Fosfomycin) 2 sachets of 8 g (of which 3g is Fosfomycin) Not all pack sizes may be marketed

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

For administration, the content of one sachet should be poured into a glass of water and 50–75ml of drinking water should be added to obtain a uniform opalescent solution. If necessary, the solution may be stirred. The solution should be taken immediately after being prepared.

ParaPharm Development Limited

Merlin House, Brunel Road

Theale

Reading RG7 4AB

United Kingdom