The following events have been observed who have taken Monural in overdose: vestibular loss, impaired hearing, metallic taste and general decline in taste perception.
In the event of an overdose, treatment should be symptomatic and supportive. Urinary elimination of the drug should be promoted through adequate administration of oral fluids.
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.
Not applicable.
Adverse reactions are listed below by System Organ Class and Frequency according to the MedDRA frequency convention and System Organ Classification:
Very common: Common: Uncommon: Rare: Very rare: Not known: | (>1/10) (>1/100 to <1/10) (>1/1,000 to <1/100) (>1/10,000 to <1/1,000) (<1/10,000) (cannot be estimated from the available data) |
| Immune system disorders | |
| Not known | anaphylactic shock allergic reaction |
| Nervous system disorder | |
| Common | headache dizziness |
| Uncommon | paraesthesia |
| Cardiac disorders | |
| Rare | tachycardia |
| Vascular disorders | |
| Not known | hypotension |
| Respiratory, thoracic and mediastinal disorders | |
| Not known | asthma |
| Gastrointestinal disorders | |
| Common | dyspepsia |
| Uncommon | diarrhoea nausea vomiting abdominal pain |
| Not known | pseudomembranous colitis |
| Skin and subcutaneous tissue disorders | |
| Uncommon | rash urticaria pruritus |
| Rare | itching |
| Not known | angioedema |
| Reproductive system and breast disorders | |
| Common | vulvovaginitis |
| General disorders and administration site conditions | |
| Uncommon | fatigue |
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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard..
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 Monural 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.
There are no non clinical data of relevance to the prescriber which are additional to that already included in other sections of this SmPC
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
Monural trometamol is an orally applicable salt of the agent Monural, a fosfonic acid epoxy.
Mechanism of action
Monural trometamol is a broad spectrum antibiotic, derived from phosphonic acid.
It inhibits the enzyme phosphoenolpyruvate transferase, which catalyses the formation of n-acetylmuramic acid from n-acetyl aminoglucose and phosphoenolpyruvate. N-acetylmuramic acid is required for the build-up of peptidoglycan, an essential component of the bacterial cell wall. Monural has a mainly bactericidal action.
PK/PD relationship
Limited data indicate that Monural most likely acts in a time- dependent manner.
Mechanisms of resistance
A resistance to Monural can be based on the following mechanisms:
- Monural is admitted into the bacterial cell actively via two different transport systems (glycerin-3-phosphate and hexose-6 transport system). In Enterobacteriaceae the glycerin-3-phosphate transport system can be changed in such a way that Monural is no longer transported into the cell.
- Another plasmid-encoded mechanism occurring in Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp. is based on the presence of a specific protein, under the effect of which Monural metabolises and is bound to glutathione (GSH).
- In staphylococci a plasmid-encoded Monural resistance also occurs. The exact mechanism of the resistance has not yet been determined.
A cross-resistance of Monural with other antibiotics classes is not known.
Break points
EUCAST clinical MIC breakpoints for oral Monural to separate susceptible (S) pathogens from resistant (R) pathogens are:
- Enterobacteriaceae S≤32mcg/ml, R>32mcg/ml
Susceptibility
The prevalence of the acquired resistance of individual species can vary locally and in the course of time. Local information on the resistance situation is therefore required - particularly for the adequate treatment of severe infections. If the effectiveness of Monural is doubtful due to the local resistance situation, a therapy consultation by experts is recommended. Particularly in the case of serious infection or therapy failure, a microbiological diagnosis indicating the pathogen and its sensitivity to Monural is recommended.
The information below gives only approximate guidance on the probability as to whether the micro-organism will be susceptible to Monurale or not.
| Commonly susceptible species: |
| Gram-positive aerobes |
| Staphylococcus saprophyticus* |
| Gram-negative aerobes: |
| Escherichia coli |
| Species for which acquired resistance may be a problem: |
| Gram-positive aerobes: |
| Enterococcus faecalis |
| Gram-negative aerobes: |
| Proteus mirabilis |
* No current data was available when the tables were published. Primary literature, standard works and therapy recommendations assume sensitivity.
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.
Monural contains Monural trometamol which is an orally well absorbed salt of Monural. It provides therapeutic concentrations of the active moiety in the urine for periods of 36 hours or more from a single dose.
Monural is orally administered after reconstitution in water, in which the formulation is completely soluble. A dose of 2g and 3g in terms of Monural, respectively in children and adults, including elderly, is rapidly absorbed from the gastrointestinal tract. These doses give peak plasma concentrations after 2 hours of 20-30 mcg/ml, serum half life is largely independent of dose.
Monural is eliminated mainly unchanged through the kidneys and this results in very high urinary concentrations (approx. 3000mg.A) within 2-4 hours. Therapeutic concentrations in urine are usually maintained for at least 36 hours.
Food delays and reduces absorption of Monural trometamol, resulting in reduced blood and urinary concentrations. However, it is unlikely that the efficacy in urinary tract infection would be seriously affected.
In patients with moderately reduced renal function (Creatinine clearance - CrCl ≤80 ml/min), including the physiological reduction in the elderly, the half life of Monural is slightly prolonged but urinary concentration remains therapeutically adequate.
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.
Older people and Patients with Renal Impairment
Monural trometamol is principally excreted by the kidney. Caution should be exercised in administering this antibiotic to patients with impaired renal function.
Antibiotic associated colitis (incl. pseudomembranous colitis) has been reported in association with the use of broad spectrum antibiotics including Monural trometamol; therefore it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of Monural trometamol. In this situation adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in this situation.
This medicine contains 1,923 g of sucrose per sachet. Patients with rare hereditary problems of fructose intolerance, glucose - galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
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 Monural (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 Monural. 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.
Monural 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 Monural 3 g is limited. The product is not recommended for children below the age of 12.
No studies on the effect on the ability to drive and use machines have been performed.
However, there are some side effects such as dizziness and fatigue associated with this product that may affect some patients' ability to drive or use machinery.
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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
The content of one sachet should be poured into a glass and 50-75 ml of water or other aqueous drink 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.
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.
