Novellmycin

Novellmycin is indicated for the treatment of acute uncomplicated lower urinary tract infections in adults, caused by pathogens sensitive to Novellmycin.

Novellmycin is indicated for periprocedural prophylaxis in diagnostic and surgical transurethral procedures.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Novellmycin is indicated in the treatment of acute lower uncomplicated urinary tract infections, caused by pathogens sensitive to fosfomycin in adult and adolescent females.

Novellmycin is also indicated for prophylaxis in diagnostic and surgical transurethral procedures.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

Adults

Uncomplicated lower urinary tract infections: one sachet (3g)

Perioperative prophylaxis of urinary tract infections: one 3g sachet 3 hours before the procedure

Paediatric population

Novellmycin trometamol in a dose of 3g is not suitable for children under the age of 12 years.

Method of administration

Novellmycin is for oral administration and should be taken on an empty stomach, either 1 hour before or at least 2 hours after meals and preferably before bedtime after emptying the bladder.

Posology

Acute lower uncomplicated urinary tract infections:

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

Prophylaxis of urinary tract infections for surgery and diagnostic procedure involving the lower urinary tract:

Adults: One Novellmycin 3 g sachet 3 hours before surgery. A second dose of 3 g may be given 24 hours after surgery.

Paediatric population

The safety and efficacy of Novellmycin 3 g in children below 12 years of age have not been established.

Method of administration

Novellmycin is for oral administration. 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.

Novellmycin is contraindicated in:

- patients with severe renal insufficiency (CLcr<10ml/min)

- patients undergoing haemodialysis

Patients with severe renal insufficiency (creatinine clearance < 10 ml/min).

Patients undergoing haemodialysis.

Older people and Patients with Renal Impairment

Novellmycin 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 Novellmycin trometamol; therefore it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of Novellmycin 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 Novellmycin (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 Novellmycin. 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.

Novellmycin 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 Novellmycin 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.

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

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 Novellmycin 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.

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.

The following events have been observed who have taken Novellmycin 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.

Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials.

ATC code: J01XX01

Novellmycin trometamol is an orally applicable salt of the agent Novellmycin, a fosfonic acid epoxy.

Mechanism of action

Novellmycin 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. Novellmycin has a mainly bactericidal action.

PK/PD relationship

Limited data indicate that Novellmycin most likely acts in a time- dependent manner.

Mechanisms of resistance

A resistance to Novellmycin can be based on the following mechanisms:

- Novellmycin 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 Novellmycin 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 Novellmycin metabolises and is bound to glutathione (GSH).

- In staphylococci a plasmid-encoded Novellmycin resistance also occurs. The exact mechanism of the resistance has not yet been determined.

A cross-resistance of Novellmycin with other antibiotics classes is not known.

Break points

EUCAST clinical MIC breakpoints for oral Novellmycin 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 Novellmycin 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 Novellmycin is recommended.

The information below gives only approximate guidance on the probability as to whether the micro-organism will be susceptible to Novellmycine or not.

* 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.

Novellmycin contains Novellmycin trometamol which is an orally well absorbed salt of Novellmycin. It provides therapeutic concentrations of the active moiety in the urine for periods of 36 hours or more from a single dose.

Novellmycin is orally administered after reconstitution in water, in which the formulation is completely soluble. A dose of 2g and 3g in terms of Novellmycin, 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.

Novellmycin 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 Novellmycin 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 Novellmycin 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.

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.

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.