Experience regarding the overdose of oral fosfomycin is limited. However cases of hypotonia, somnolence, electrolytes disturbances, thrombocytopenia and hypoprothrombinemia have been reported with parenteral use of fosfomycin.
In the event of overdose, treatment should be symptomatic and supportive. Rehydration is recommended to promote urinary elimination of the drug.
Three years.
After reconstitution in water, the solution is stable at room temperature for 24 hours.
Patients with severe renal insufficiency (creatinine clearance < 10 ml/min).
Patients undergoing haemodialysis.
Not applicable.
Mandarin flavour
Orange flavour
Saccharin
Sucrose
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 Monuril from either clinical-trial or post-marketing experiences.
The displayed frequency categories use 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.
| System organ class | Adverse drug reactions | |||
| Common | Uncommon | Rare | Not known | |
| Infections and infestations | Vulvovaginitis | |||
| Immune system disorders | Anaphylactic reactions including anaphylactic shock, hypersensitivity | |||
| Nervous system disorders | Headache, dizziness | |||
| Gastrointestinal disorders | Diarrhoea, nausea | Vomiting, abdominal pain | Antibiotic-associated colitis | |
| Skin and subcutaneous tissue disorders | Rash, urticaria, pruritus | Angioedema | ||
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 national reporting system website: www.mhra.gov.uk/yellowcard.
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 trometamol.
Pharmacotherapeutic group: Antibacterials for systemic use - other antibacterials.
ATC code: J01XX01
Mode of action:
Fosfomycin acts on at the first stage of bacterial wall synthesis. It inhibits the phosphoenolpyruvate transferase enzyme, thereby irreversibly blocking the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate. Fosfomycin is actively transported into the bacterial cell via two different transport systems (the sn-glycerol-3-phosphate and hexose-6 transport systems). It can also reduce bacterial adhesion to bladder mucosa, which can be a predisposing factor for recurring infections. Its mechanism of action explains the lack of cross-resistance with other antibiotics.
Commonly susceptible species:
Citrobacter spp
Escherichia coli
Klebsiella oxytoca
Proteus mirabilis
Staphylococcus aureus
Species in which acquired resistance may be a problem:
Enterococcus faecalis
Enterobacter cloacae
Pseudomonas aeruginosa
Serratia marcescens
Inherently resistant species:
Bacteroides spp.
Resistance:
Main mechanism of resistance is a chromosomal mutation causing an alteration of the bacterial fosfomycin transport systems.
Susceptibility testing Break points Version 4.0, valid from 2014-01-01
EUCAST clinical MIC breakpoints for oral fosfomycin to separate susceptible (S) pathogens from resistant (R) pathogens are:
- Enterobacteriaceae S≤ 32 mcg/ml, R> 32 mcg/ml
- For other species MIC breakpoint not defined.
Clinical efficacy against specific pathogens:
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable.
Pharmacokinetic (PK)/pharmacodynamic (PD) relationship:
Limited data indicate that fosfomycin most likely acts in a time-dependent manner.
Absorption
After single-dose oral administration, fosfomycin trometamol has an absolute bioavailability of about 34-41%. Rate and extent of absorption are reduced by food.
Distribution
Fosfomycin is distributed to tissues including the kidneys and bladder wall. Fosfomycin is not bound to plasma proteins and crosses the placental barrier.
Biotransformation and Elimination
Fosfomycin does not appear to be metabolised and is excreted unchanged mainly via the kidneys by glomerular filtration with an elimination half-life of about 4 hours after oral administration.
Special populations
In patients with impaired renal function, the elimination half-life is increased proportionally to the degree of renal insufficiency.
In older people fosfomycin clearance is reduced in line with the age related reduction in renal function.
20/01/2016
ZAMBON S.p.A.
Via Lillo Del Duca, 10
20091 Bresso (Milan) - Italy
Tel: +39 02 665 241
Fax: +39 02 665 01 492
Store away from direct sunlight.
Sachets are a four layer laminate: paper, polyethylene, aluminium, polyethylene.
Sachets are supplied in cardboard outer containing 1 sachet, 2 sachets or 5 sachets.
Not all pack sizes may be marketed.
PL 31654/0006
Pregnancy
At the present time, single-dose antibacterial treatments are not suitable to treat urinary tract infections in pregnant women.
However, for fosfomycin trometamol, animal studies do not indicate reproductive toxicity. A large amount of data concerning effectiveness of fosfomycin during pregnancy is available. Only moderate amount of safety data on pregnant women is available and does not indicate any malformative or foetal/neonatal toxicity of fosfomycin.
The use of Monuril may be considered during pregnancy, if necessary.
Breast-feeding
Fosfomycin is excreted into human milk at low level after a single injection. Therefore fosfomycin can be used during breastfeeding, after a single oral dose.
Fertility
No effect on fertility has been reported in animal studies. No data are available in human.
Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during fosfomycin treatment and may be life-threatening. If such reaction occurs, fosfomycin should never be re-administrated and an adequate medical treatment is required.
Antibiotic-associated diarrhoea has been reported with use of nearly all antibacterial agents, including fosfomycin and may range in severity from mild diarrhoea to fatal colitis. Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Monuril (including several weeks after treatment), may be symptomatic of Clostridium difficile-associated disease (CDAD). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with Monuril. If CDAD is suspected or confirmed, appropriate treatment should be initiated without delay. Anti-peristaltic medicinal products are contra-indicated in this clinical situation.
Renal insufficiency: urinary concentrations of fosfomycin remain effective for 48 hours after a usual dose if creatinine clearance is above 10 ml/min.
Monuril contains sucrose. Its use is not recommended in patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.
Paediatric population
Experience in children with Monuril 3 g is limited. The product is not recommended for children below the age of 12.
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.
The dose must be dissolved in a glass of water and administered soon after dissolving.
Any unused product or waste material should be disposed in accordance with local requirements.
18/03/1994 / 19/09/2008
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 may delay the absorption of the active ingredient of Monuril, 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 antivitamin K antagonists activity have been reported in patients receiving antibiotics. 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.
