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1. Fosfomycin 3g Granules For Oral Solution
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Document: spc-doc_PL 12762-0508 change

• spc-doc_PL 12762-0508
• spc-doc_PL 31513-0007

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fosfomycin 3 g granules for oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Fosfomycin trometamol

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

Excipient(s) 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 is indicated for the treatment of acute uncomplicated lower urinary tract infections in adults, caused by pathogens sensitive to fosfomycin.

Fosfomycin 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

Paediatric population

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

Method of administration

Fosfomycin 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. 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.

4.3 Contraindications

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

Fosfomycin is contraindicated in:

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

•    patients undergoing haemodialysis

4.4 Special warnings and precautions for use

Older people 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).

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) have shown no hazard to the fetus.

Previous studies in the rat showed fetal 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 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 use 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:

(>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..

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

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.

For storage conditions after reconstitution of the medicinal product, see section 6.3

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 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.

7 MARKETING AUTHORISATION HOLDER

Mercury Pharmaceuticals Limited Capital House, 1st Floor,

85 King William Street,

London EC4N 7BL,

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 12762/0508

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/07/2015

10    DATE OF REVISION OF THE TEXT

30/07/2015

1

   Another plasmid-encoded mechanism occurring in Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp. is based on the presence of a specific