Fosfomycin 3g Granules For Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fosfomycin 3g granules for oral solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Fosfomycin trometamol
Each single-dose sachet contains 5631mg fosfomycin trometamol, equivalent to 3 g fosfomycin.
Excipients with known effect: Each single-dose sachet contains 1.923 g of sucrose. 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 CLINICAL PARTICULARS
4.1 Therapeutic indications
Fosfomycin 3g granules for oral solution is indicated for the treatment of acute uncomplicated lower urinary tract infections in adults, caused by pathogens sensitive to fosfomycin.
Fosfomycin 3g granules for oral solution 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.
4.2 Posology and method of administration Posology
Adults
Uncomplicated lower urinary tract infections: one sachet (3g)
Perioperative prophylaxis of urinary tract infections: one 3g sachet 3 hours before the procedure and one 3 g sachet 24hours after surgery.
Paediatric population
Fosfomycin trometamol in a dose of 3g is not suitable for children under the age of 12 years.
Method of administration
Fosfomycin 3g granules for oral solution is for oral administration and should be taken on an empty stomach, preferably before bedtime after emptying the bladder. The contents of a sachet should be dissolved in a glass of water and taken immediately after its preparation.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Elderly and Patients with Renal Impairment
Fosfomycin trometamol is principally excreted by the kidney. Caution should be exercised in administering this antibiotic to patients with impaired renal function (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Fosfomycin 3g granules for oral solution is contraindicated in:
• patients with severe renal insufficiency (CLcr<10ml/min)
• patients undergoing haemodialysis
4.4 Special warnings and precautions for use
Meals may delay the absorption of the active ingredient causing a slight decrease in Peak blood and urine levels Fosfomycin 3g granules for oral solution should therefore be taken on an empty stomach either 1 hour before or at least 2 hours after meals.
Keep out of the reach of children.
Antibiotic associated colitis (incl. pseudomembranous colitis) has been reported in association with the use of broad spectrum antibiotics including fosfomycin trometamol; therefore it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of fosfomycin 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.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant administration of metoclopramide has been shown to lower serum and urinary concentrations and should be avoided.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are limited data from the use of fosfomycin in pregnant women. Animal studies with fosfomycin trometamol (the form used in Fosfomycin 3g granules for oral solution) have shown no hazard to the fetus.
Previous studies in the rat showed foetal toxicity following administration of the calcium and sodium salts of fosfomycin at the maximum doses tested (approximately 25 times the therapeutic dose). However, toxicity to the foetus was not observed at lower doses in the rat or at any of the doses tested in the rabbit. Fosfomycin should only be used in pregnancy when the expected benefits outweigh the risk.
Breast-feeding
Fosfomycin is excreted in breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from { Fosfomycin 3g granules for oral solution } therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
No clinical data are available; hence the potential risk for humans is unknown.
4.7 Effects on ability to drive and use machines
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 operate machinery (see section 4.8).
4.8 Undesirable effects
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 the national reporting system listed in Appendix V
4.9 Overdose
The following events have been observed who have taken fosfomycin 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials. ATC code: J01XX01
Fosfomycin trometamol is an orally applicable salt of the agent fosfomycin, a fosfonic acid epoxy.
Mechanism of action
Fosfomycin 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. Fosfomycin has a mainly bactericidal action.
PK/PD relationship
Limited data indicate that fosfomycin most likely acts in a time- dependent manner.
Mechanisms of resistance
A resistance to fosfomycin can be based on the following mechanisms:
• Fosfomycin 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 fosfomycin is no longer transported into the cell. 1
• In staphylococci a plasmid-encoded fosfomycin resistance also occurs. The exact mechanism of the resistance has not yet been determined.
A cross-resistance of fosfomycin with other antibiotics classes is not known.
Break points
EUCAST clinical MIC breakpoints for oral fosfomycin to separate susceptible (S) pathogens from resistant (R) pathogens are:
• Enterobacteriaceae S<32mcg/ml, R>32mcg/ml
• For other species MIC breakpoint not defined.
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 fosfomycin 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 fosfomycin is recommended.
The information below gives only approximate guidance on the probability as to whether the micro-organism will be susceptible to fosfomycine or not.
Commonly susceptible species: Gram-positive aerobes
Staphylococcus saprophyticus1
Gram-negative aerobes:
Escherichia coli
Species for which acquired resistance may be a problem: Gram-positive aerobes:
Enterococcus faecalis
Gram-negative aerobes:
Proteus mirabilis 2
5.2 Pharmacokinetic properties
Fosfomycin contains fosfomycin trometamol which is an orally well absorbed salt of fosfomycin. It provides therapeutic concentrations of the active moiety in the urine for periods of 36 hours or more from a single dose.
Fosfomycin is orally administered after reconstitution in water, in which the formulation is completely soluble. A dose of 2g and 3g in terms of fosfomycin, 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.
Fosfomycin 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 fosfomycin 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 fosfomycin is slightly prolonged but urinary concentration remains therapeutically adequate.
5.3 Preclinical safety data
There are no non clinical data of relevance to the prescriber which are additional to that already included in other sections of this SmPC
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Orange flavour consisting of: maltodextrin, dextrose monohydrate, acacia (E414), anhydrous citric acid (E330), butylhydroxyanisole (E320).
Saccharin sodium
Sucrose
Calcium hydroxide
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.
The content of one sachet should be poured into a glass of water so as to obtain a uniform opalescent solution. If necessary, the solution may be stirred. The solution should be taken immediately after being prepared.
7 MARKETING AUTHORISATION HOLDER
Exeltis Poland Sp. z o.o. ul. gen. Jozefa Zaj^czka 9 01-518 Warszawa
8 MARKETING AUTHORISATION NUMBER(S)
PL 3513/0007
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
31/05/2013
10 DATE OF REVISION OF THE TEXT
12/04/2016
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 fosfomycin metabolises and is bound to glutathione (GSH).
No current data was available when the tables were published. Primary literature, standard works and therapy recommendations assume sensitivity.