4.1. Therapeutic indications

Monuril is indicated for (see section 5.1):

- the treatment of acute, uncomplicated cystitis in women and female adolescents

- perioperative antibiotic prophylaxis for transrectal prostate biopsy in adult man

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

4.2. Posology and method of administration

Posology

Acute, uncomplicated cystitis in women and female adolescents (>12 years of age): 3 g fosfomycin once

Perioperative antibiotic prophylaxis for transrectal prostate biopsy: 3 g fosfomycin 3 hours prior to the procedure and 3 g fosfomycin 24 hours after the procedure.

Renal impairment:

Use of Monuril is not recommended in patients with renal impairment (creatinin clearance < 10 ml/min, see section 5.2).

Paediatric population

The safety and efficacy of Monuril in children aged below 12 years of age have not been established.

Method of administration

For oral use.

For the indication of acute, uncomplicated cystitis in women and female adolescents 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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during fosfomycin treatment (see sections 4.3 and 4.8). If such reactions occur, treatment with fosfomycin must be discontinued immediately and adequate emergency measures must be initiated.

Clostridioides difficile -associated diarrhea

Clostridioides difficile-associated colitis and pseudo-membranous colitis have been reported with fosfomycin and may range in severity from mild to life-threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or subsequent to the administration of fosfomycin. Discontinuation of therapy with fosfomycin and the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Paediatric population

The safety and efficacy of Monuril in children below 12 years of age have not been established. Therefore, this medicine should not be used in this age group (see section 4.2).

Persistent infections and male patients

In case of persistent infections, a thorough examination and a re-evaluation of the diagnosis is recommended as this is often due to complicated urinary tract infections or the prevalence of resistant pathogens (e.g. Staphylococcus saprophyticus, see section 5.1). In general, urinary tract infections in male patients have to be considered as complicated UTIs for which this medicinal product is not indicated (see section 4.1).

Excipients

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per sachet that is to say essentially 'sodium-free'.

Sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not use this medicine.

Sulphites

May rarely cause severe hypersensitivity reactions and bronchospasm.

4.5. Interaction with other medicinal products and other forms of interaction

Metoclopramide:

Concomitant administration of metoclopramide has been shown to lower serum and urinary concentrations of fosfomycin and should be avoided.

Other medicinal products that increase gastrointestinal motility may produce similar effects.

Food effect:

Food may delay the absorption of fosfomycin, with consequent slight decrease in peak plasma levels and urinary concentrations. It is therefore preferable to take the medicinal product on an empty stomach or about 2 – 3 hours after meals.

Specific problems concerning the alteration in INR:

Numerous cases of increased oral anticoagulant activity have been reported in patients receiving antibiotic therapy. 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.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy:

Only limited data on the safety of fosfomycin treatment during 1st trimester of pregnancy (n=152) are available. These data do not raise any safety signal for teratogenicity so far. Fosfomycin crosses the placenta.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Monuril should only be used during pregnancy, if clearly necessary.

Breast-feeding:

Fosfomycin is excreted in human milk in low quantities. If clearly necessary, a single dose of oral fosfomycin can be used during breast-feeding.

Fertility:

No data in humans are available. In male and female rats oral administration of fosfomycin up to 1000 mg/kg/d did not impair fertility.

4.7. Effects on ability to drive and use machines

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 (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

The following table displays adverse reactions that have been reported with the use of fosfomycin trometamol from either clinical-trial or post-marketing experiences.

Undesirable effects are listed by body system and frequency using 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

Not known

Infections and infestations

Vulvovaginitis

Immune system disorders

Anaphylactic reactions including anaphylactic shock, hypersensitivity (see section 4.4)

Nervous system disorders

Headache, dizziness

Gastrointestinal disorders

Diarrhoea, nausea, dyspepsia, abdominal pain

Vomiting

Antibiotic- associated colitis (see section 4.4)

Skin and subcutaneous tissue disorders

Rash, urticaria, pruritus

Angioedema

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 website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Experience regarding the overdose of oral fosfomycin is limited. Cases of hypotonia, somnolence, electrolytes disturbances, thrombocytopenia and hypoprothrombinemia have been reported with parenteral use of fosfomycin.

In the event of overdose, the patient must be monitored (particularly for plasma/serum electrolyte levels), and treatment should be symptomatic and supportive. Rehydration is recommended to promote urinary elimination of the active substance. Fosfomycin is effectively cleared from the body by haemodialysis with a mean elimination half-life of approximately 4 hours.