Consumer medicine information

Monurol

Fosfomycin

BRAND INFORMATION

Brand name

Monurol Granules for oral solution

Active ingredient

Fosfomycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Monurol.

What is in this leaflet

This leaflet answers some common questions about MONUROL. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking MONUROL against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What MONUROL is used for

MONUROL contains the active ingredient fosfomycin trometamol and it belongs to a group of medicines called antibiotics.

MONUROL is only used to treat uncomplicated infections of the bladder in females. It works by killing bacteria which can cause infections. Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

MONUROL is not addictive.

It is available only with a doctor's prescription.

Before you take MONUROL

When you must not take it

Do not take MONUROL if you:

  • are allergic to fosfomycin trometamol or any of the other ingredients listed at the end of this leaflet
  • have severe kidney problems (creatinine clearance below 10 ml/min)
  • are undergoing haemodialysis.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not give this medicine to a child under the age of 12 years.

Safety and effectiveness in children younger than 12 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • an intolerance to some sugars
  • previously had diarrhoea after taking any antibiotics
  • kidney problems, but your creatinine clearance is above 10 ml/min.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

Your doctor can discuss with you the risks and benefits involved.

If you are pregnant, the active ingredient in MONUROL can cross the placenta and MONUROL can pass into the foetus. There is a possibility that your baby may be affected.

The active ingredient in MONUROL passes into breast milk and there is a possibility that your baby may be affected.

If you have not told your doctor about any of the above, tell him/her before you start taking MONUROL.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and MONUROL may interfere with each other. These include:

  • metoclopramide or other drugs that increase the movement of food through the stomach and intestines, because they may reduce the uptake of fosfomycin trometamol by your body
  • anticoagulants, as their ability to prevent your blood from clotting might be altered by fosfomycin trometamol and other antibiotics.

These medicines may be affected by MONUROL or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take MONUROL

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The recommended dose is one sachet of MONUROL, given once, as a single dose.

How to take it

Dissolve the content of one sachet in a glass of water and drink immediately.

MONUROL should not be taken in its dry form. Always mix MONUROL with water before ingesting. Do not use hot water.

MONUROL should be taken immediately after dissolving in water.

When to take it

Take your medicine on an empty stomach, (2-3 hours before or 2-3 hours after a meal), preferably before going to bed and after emptying the bladder.

How long to take it

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

If you take too much (overdose)

If you accidentally take more than your prescribed dose, contact your doctor or pharmacist.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much MONUROL. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include changes in hearing and taste perception.

While you are taking MONUROL

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking MONUROL.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take MONUROL to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how MONUROL affects you.

This medicine may cause dizziness in some people. If you have experience this symptom, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking MONUROL.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • dizziness
  • diarrhoea (if it becomes severe consult your doctor immediately)
  • nausea, vomiting
  • indigestion (dyspepsia)
  • infection of the female genital organs with symptoms like inflammation, irritation, itching (vulvovaginitis)
  • tingling of the skin mouth, cheeks and/or tongue (paraesthesias)
  • temporary reduced, altered or metallic taste sensation
  • abdominal pain
  • rash, urticaria, pruritus
  • fatigue
  • asthma with symptoms such as wheezing, shortness of breath, coughing and chest tightness
  • low blood pressure (hypotension).

Tell your doctor as soon as possible if you notice any of the following:

  • anaphylactic shock, a life threatening type of allergic reaction
  • Symptoms include a sudden onset of rash, itching or hives on the skin and or shortness of breath, wheezing or difficulty in breathing
  • swelling of the face, lips, tongue or throat with breathing difficulties (angioedema)
  • faster heart beat (tachycardia)
  • mild to severe abdominal cramps, bloody stools, diarrhoea and/or fever may mean that you have an infection of the large intestine (antibiotic-associated colitis).

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking MONUROL

Storage

Keep your sachet in the carton until it is time to take them.

If you take the sachet out of the carton they may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store MONUROL or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

MONUROL is presented as white granules for oral solution in a single use sachet.

The sachet is a four layer laminate, comprising of:
paper/polyethylene/aluminium/polyethylene.

MONUROL sachet is supplied in an outer cardboard carton, one sachet per carton.

Ingredients

MONUROL contains 5.631 g of fosfomycin trometamol as the active ingredient, equivalent to 3 g of fosfomycin.

  • tangerine flavour
  • orange juice flavour
  • saccharin
  • sucrose (MONUROL contains 2.213 g of sucrose).

This medicine does not contain lactose, gluten, tartrazine or any other azo dyes.

Supplier

Mayne Pharma International Pty Ltd
ABN 88 007 870 984
1538 Main North Road
Salisbury South SA 5106

Australian Registration Number

AUST R 278658

This leaflet was prepared in September 2017.

CMI Version Number: 1.0

BRAND INFORMATION

Brand name

Monurol Granules for oral solution

Active ingredient

Fosfomycin

Schedule

S4

 

1 Name of Medicine

Fosfomycin trometamol.

6.7 Physicochemical Properties

Chemical structure.

Chemically, fosfomycin trometamol is 2-hydroxy-1,1-bis (hydroxymethyl) ethylammonium (2R,3S)-(3-methyloxiran-2-yl) phosphonate and has the following chemical structure:
Molecular formula: C7H18NO7P.
Relative molecular mass: 259.2.

CAS number.

78964-85-9.

2 Qualitative and Quantitative Composition

One sachet of Monurol granules for oral solution contains 5.631 g of fosfomycin trometamol equivalent to 3.0 g fosfomycin.
Fosfomycin trometamol is a white or nearly white crystalline powder. It is very soluble in water, slightly soluble in 95% methanol and ethanol, almost insoluble in anhydrous acetone, in ether and in chlorinated solvents.

Excipients with known effect.

Monurol contains sugars (as sucrose) and saccharin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Monurol contains 3 g fosfomycin (as fosfomycin trometamol), presented as white granules for oral solution in single use sachet.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fosfomycin inhibits 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). Fosfomycin has a mainly bactericidal action. It can also reduce bacterial adhesion to bladder mucosa, which can be a predisposing factor for recurring infections. As this mechanism of action is unique to fosfomycin cross-resistance is not expected with other antibiotics.

Microbiology.

There has been very limited fosfomycin susceptibility testing performed in Australia to date. Recommendations are based on studies performed overseas.

Activity in vitro.

Bacterial species commonly susceptible to fosfomycin using European Committee on Antimicrobial Susceptibility Testing (EUCAST) or Clinical and Laboratory Standard Institute (CLSI) susceptibility testing guidelines: Escherichia coli, Proteus spp., Klebsiella spp., Citrobacter spp., Enterococcus faecalis.
Bacterial species variably susceptible or resistant to fosfomycin using EUCAST or CLSI susceptibility testing guidelines: Enterobacter spp., Serratia marcescens, Providencia spp.
Bacterial species frequently resistant to fosfomycin using EUCAST or CLSI susceptibility testing guidelines: Morganella morganii.
Oral fosfomycin is not recommended in the treatment of the following bacterial species which do not have EUCAST or CLSI susceptibility testing guidelines: Staphylococcus saphrophyticus, Pseudomonas aeruginosa, Enterococcus faecium, Staphylococcus aureus, Acinetobacter spp., Stenotrophomonas maltophilia, Bacteroides spp. and other anaerobic bacteria.

Resistance.

Main mechanism of resistance is a chromosomal mutation causing an alteration of the bacterial fosfomycin transport systems. Plasmid-encoded mechanisms of resistance to fosfomycin have also been documented. (See Table 2.)
Based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria, fosfomycin trometamol single 3 g oral dose is calibrated for the treatment of acute uncomplicated urinary tract infection (UTI) caused by Enterobacteriaceae. MIC breakpoints are ≤ 32 (less than or equal than) mg/L (S) and > 32 mg/L (R). EUCAST disc diffusion zone diameter breakpoints for E. coli only are > 24 mm (S) and < 24 mm (R). For other Enterobacteriaceae, an MIC method should be used. All methods require glucose-6-phosphate supplementation.
There are no EUCAST guidelines for other urinary pathogens such as Pseudomonas, Staphylococcus saphrophyticus, or Enterococcus spp.
Based on Clinical and Laboratory Standard Institute (CLSI) criteria, only E. coli and Enterococcus faecalis from urinary tract isolates are calibrated. MIC breakpoints for both are < 64 mg/L (S), 128 mg/L (I), and > 256 mg/L (R). Disc and agar dilution MIC methods are approved provided there is supplemental glucose-6-phosphate. CLSI does not recommend broth dilution fosfomycin susceptibility testing.
There are no CLSI guidelines for any other bacteria apart from E. coli and Enterococcus faecalis.

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.
Oral fosfomycin should be used where there is resistance to other suitable antibiotics, including trimethoprim, cephalexin and amoxycillin/clavulanic acid.

Pharmacokinetic (PK)/pharmacodynamic (PD) relationship.

Limited data indicate that fosfomycin most likely acts in a concentration-dependent manner. There are no known PK/PD breakpoints for fosfomycin.

Clinical trials.

In three phase 3 prospective parallel multi-centre double-blind double-dummy randomised trials of acute uncomplicated urinary tract infection (UTI) performed in the 1990s, a single 3 g oral dose of Monurol was compared to three other oral antibiotics (see Table 3). The study population consisted of female patients with symptoms and signs of acute lower UTI of less than 4 days duration, no manifestations of upper tract infection (e.g. flank pain, chills, fever), no history of recurrent urinary tract infections (20% of patients in the clinical studies had a prior episode of acute cystitis within the preceding year), no known structural abnormalities, no clinical or laboratory evidence of hepatic dysfunction, and no known or suspected CNS disorders, such as epilepsy, or other factors which would predispose to seizures. In the first two studies (US-MON-01 comparator arm ciprofloxacin and US-MON-02 comparator arm trimethoprim/sulphamethoxazole), adult females aged 18 years and older were enrolled and patients with renal dysfunction (defined as serum creatinine clearance < 30 mL/min) were excluded. In the third study (US-MON-03, nitrofurantoin comparator), females aged 12 years and older were enrolled and patients with severe renal dysfunction (defined as serum creatinine clearance < 60 mL/min) were excluded. In all three studies, pregnancy, immunosuppression and neutropenia were exclusion criteria.
In these studies, the following clinical success (resolution of symptoms) and microbiologic eradication rates were obtained (Table 3).
In the 3 pivotal studies, median age of patients enrolled was 27-32 years (fosfomycin) and 27-31.5 years (comparator arms). In all 3 studies, approximately half the patients were aged 30 years or less. The most common pathogen in the three pivotal studies was E. coli, which caused 82-86% of UTIs. Table 4 shows microbiological cure rates from pooled data from the 3 studies by pathogen.
There have been no other phase 3 prospective, parallel, multicentre, double-blind, double-dummy randomised efficacy and safety trials for the treatment of acute uncomplicated UTI since the three pivotal studies US-MON-01, US-MON-02, and US-MON-03 performed in the 1990s.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, fosfomycin is well absorbed from the gut and has an absolute bioavailability of about 35-40%. Food delays absorption, not influencing urinary concentrations.

Distribution.

Fosfomycin is distributed to the kidneys, bladder wall, prostate and seminal vesicles. Sustained concentrations of fosfomycin higher than the minimum inhibitory concentrations (MIC) are obtained in urine for 24-48 hours after oral administration.
Fosfomycin does not bind to plasma proteins, fosfomycin has been shown to cross the placental barrier in humans and animals.

Metabolism.

Fosfomycin does not appear to be metabolised.

Excretion.

Fosfomycin is excreted unchanged mainly via the kidneys by glomerular filtration (40-50% of the dose is found in the urine) with an elimination half-life of about 4 hours and to a lesser extent in faeces (18-28% of the dose). The appearance of a second serum peak 6 and 10 hours after drug intake suggests that the drug is subject to enterohepatic recirculation.

Special populations.

Elderly.

The pharmacokinetic features of fosfomycin are not modified by age (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Pregnancy.

The pharmacokinetic features of fosfomycin do not appear to be modified by pregnancy in a study of 4 pregnant patients (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Hepatic impairment.

The pharmacokinetic features of fosfomycin have not been studied in patients with impaired hepatic function. However, fosfomycin does not undergo hepatic metabolism and clearance is known to be predominantly renal with urinary excretion. Limited studies confirm that there is an enterohepatic recirculation which does not influence bioavailability (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Renal impairment.

The pharmacokinetics of fosfomycin trometamol have not been studied in patients undergoing peritoneal dialysis or haemofiltration.
In 5 anuric patients undergoing haemodialysis, the t1/2 of fosfomycin during haemodialysis was 40 hours. In patients with varying degrees of renal impairment (creatinine clearances varying from 54 mL/min to 7 mL/min), the t1/2 of fosfomycin increased from 11 hours to 50 hours. The percent of fosfomycin recovered in urine decreased from 32% to 11% indicating that renal impairment significantly decreases the excretion of fosfomycin.
The drug accumulates in patients with severe renal impairment but the significance of this is unknown. Linear relationships have been established between fosfomycin pharmacokinetic parameters and glomerular filtration rate.
See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Fosfomycin was not found to be genotoxic under in vitro (bacterial reverse mutation assay, mammalian mutation assay, chromosomal aberration test) or in vivo conditions (mouse micronucleus test).

Carcinogenicity.

Carcinogenicity studies in rodents have not been conducted. Based on the short-term use of fosfomycin and the lack of evidence of genotoxicity, fosfomycin is not anticipated to be carcinogenic.

4 Clinical Particulars

4.1 Therapeutic Indications

Monurol is indicated only for the treatment of acute uncomplicated lower urinary tract infections (acute cystitis) in females above 12 years of age caused by the following susceptible pathogens: Enterobacteriaceae (including Escherichia coli), Enterococcus faecalis.
Monurol is not indicated for the treatment of pyelonephritis or perinephric abscess or where resistance is likely (previous treatment failure, infection due to non-susceptible organism).
Appropriate culture and susceptibility studies should be performed to identify the causative organism(s) and determine its (their) susceptibility to Monurol. However, therapy may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued. Consideration should be given to the relevant clinical guidelines on the appropriate use of antibacterial agents.

4.3 Contraindications

Hypersensitivity to fosfomycin trometamol or to any of the excipients.
Patients with severe renal insufficiency (creatinine clearance < 10 mL/min).
Patients undergoing haemofiltration, haemodialysis or peritoneal dialysis.

4.4 Special Warnings and Precautions for Use

General.

Do not use more than one single dose of Monurol to treat a single episode of acute cystitis. Repeated daily doses of Monurol did not improve the clinical success or microbiological eradication rates compared to single dose therapy, but did increase the incidence of adverse events.

Gender.

The three pivotal trials US-MON-01, US-MON-02 and US-MON-03 were conducted in female patients only. However, there is extensive early clinical trial and post-marketing experience in males. There do not appear to be any gender-associated differences in the safety profile of Monurol. Efficacy data in male patients with urinary tract infection (UTI) is limited so Monurol is not recommended in males.

Hypersensitivity.

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during fosfomycin treatment and may be life-threatening (see Section 4.8 Adverse Effects (Undesirable Effects)). If such reaction occurs, fosfomycin should never be re-administrated and an adequate medical treatment is required.

Antibiotic-associated diarrhoea.

Antibiotic-associated diarrhoea has been reported with use of nearly all antibacterial agents, including fosfomycin (see Section 4.8 Adverse Effects (Undesirable Effects)) and may range in severity from mild diarrhoea to fatal colitis. Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Monurol (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 Monurol. If CDAD is suspected or confirmed, appropriate treatment should be initiated without delay.

Sucrose content.

Monurol contains sucrose. Its use is not recommended in patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

Food.

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

Use in hepatic impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

Urinary concentrations of fosfomycin remain effective for 48 hours after a usual dose if creatinine clearance is above 10 mL/min.
In consideration of the safety profile of the drug and of single dose treatment, in patients with mild to moderate renal impairment (define as creatinine clearance > 10 mL/min) it is not necessary to adjust the dose but these patients have to be carefully monitored.
Due to reduced excretion of drug and limited data, fosfomycin trometamol is contraindicated in severe renal failure (creatinine clearance < 10 mL/min), haemodialysis, peritoneal dialysis and haemofiltration.
See Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

Fosfomycin may be given in the elderly. In elderly patients with good renal function, pharmacokinetics, efficacy and safety appear similar to younger adults. For elderly patients with age-related or other renal insufficiency, see Section 5.2 Pharmacokinetic Properties, Special populations.

Paediatric use.

Experience in children with Monurol 3 g is limited. The product is not recommended for children below the age of 12.

Effects on laboratory tests.

In post-marketing surveillance, three cases of increased INR (prothrombin time) and two cases of decreased INR (prothrombin time) were reported. No further clinical information is available regarding these patients. As fosfomycin does not bind to plasma proteins and does not undergo metabolism, an interaction with anticoagulant drugs of the coumarin type such as warfarin is not anticipated, although fosfomycin has not been studied in patients taking anticoagulants. Recommend monitoring of coagulation in patients receiving coumarins.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant administration of metoclopramide has been shown to lower serum and urinary concentrations of fosfomycin and should be avoided.
Other drugs that increase gastrointestinal motility may produce similar effects.
Cimetidine does not alter the pharmacokinetics of fosfomycin.
Interaction studies with metoclopramide and cimetidine have only been performed in healthy adult volunteers aged 20 years and over. No other drugs have been studied for potential interactions with fosfomycin. No drug interaction studies have been performed in humans aged less than 20 years.
Concomitant usage with urinary alkalinisers is not recommended. Monurol is most bactericidal at typical urinary pH. Also, potential for resistance development appears less at acid pH.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fosfomycin had no effect on fertility in male and female rats at doses up to 1000 mg/kg/day (3-times the clinical dose relative to body surface area). No data are available in humans.
(Category B2)
Fosfomycin was not found to be teratogenic in rats and rabbits when tested at doses of up to 1000 mg/kg/day and 500 mg/kg/day, respectively (3- and 3.8-times the clinical dose relative to body surface area, respectively). Fetotoxicity was observed in rabbits at doses ≥ 1000 mg/kg/day, which was secondary to maternotoxicity (maternal deaths and body weight losses). No adverse findings were reported in peri-postnatal studies in rats treated at up to 1000 mg/kg/day (3-times the clinical dose relative to body surface area).
In early clinical trials and in the post-marketing period, at least 1400 pregnant human patients are known to have received fosfomycin during pregnancy, usually a 3 g single oral dose. Most patients received the drug during the second and third trimesters. There is no evidence based on review of human data that fosfomycin is associated with adverse foetal or maternal outcomes or teratogenicity. At the present time, single-dose antibacterial treatments are not considered suitable to treat urinary tract infections in pregnant women (see Section 5.2 Pharmacokinetic Properties, Special populations).
Fosfomycin is excreted in breast milk.
Monurol therapy should therefore not be used in breastfeeding mothers unless the potential benefit outweighs the potential risks.

4.8 Adverse Effects (Undesirable Effects)

The majority of clinical trials have been conducted in adult or adolescent females aged 12 years or above. The most common adverse reactions following the single 3 g dose of fosfomycin trometamol involved the gastrointestinal tract, mainly diarrhoea. These events were usually self-limited in duration and resolve spontaneously. Table 1 lists drug-related adverse events which occurred in 1% or more of fosfomycin recipients in the three pivotal trials.
The following list displays ADRs that have been reported with the use of Monurol 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).

Infections and infestations.

Common: vulvovaginitis.

Immune system disorders.

Not known: anaphylactic reactions including anaphylactic shock, hypersensitivity.

Nervous systems disorders.

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: diarrhoea, nausea, dyspepsia.
Uncommon: vomiting, abdominal pain, anorexia, dry mouth, flatulence.
Not known: antibiotic-associated colitis (see Section 4.4 Special Warnings and Precautions for Use, Antibiotic-associated diarrhoea), oral paraesthesias (temporary tingling of mouth, tongue and cheek), temporary alterations of taste (dysgeusia and hypogeusia).

Skin and subcutaneous tissue disorders.

Uncommon: rash, urticaria, pruritus.
Not known: angioedema.

General disorders and administration site conditions.

Uncommon: fatigue, asthenia.
One patient in a pivotal trial developed unilateral optic neuritis, considered possibly related to Monurol therapy.

Reporting suspected adverse events.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The recommended dose for the treatment of acute uncomplicated lower urinary tract infections (acute cystitis) is a single Monurol 3 g sachet in women above 12 years of age.
Monurol is for oral administration.
It should be taken on an empty stomach or about 2 - 3 hours after meals, preferably before bedtime and after emptying the bladder.
The dose should be dissolved into a glass of water and taken immediately after its preparation.
Monurol should not be taken in its dry form. Always mix Monurol with water before ingesting. Do not use hot water. Monurol should be taken immediately after dissolving in water.

Paediatric population.

The safety and efficacy of Monurol 3 g in children below 12 years have not been established. No data are available.

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.

4.9 Overdose

In acute toxicity studies a single oral dose of 5000 mg/kg was well tolerated both in mice and rats and a single dose of 2000 mg/kg did not produce changes in rabbits and dogs.
Repeated dose studies by oral route showed that the no-effect dose was between 100 and 200 mg/kg after 4 weeks of treatment in dogs and rats, respectively.
Experience regarding the overdose of oral fosfomycin is limited. The following events have been observed in patients who have taken Monurol 3 g in overdose: vestibular loss, impaired hearing, metallic taste, and general decline in taste perception.
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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

6 Pharmaceutical Particulars

6.1 List of Excipients

Each sachet of Monurol also contains the following excipients: Tangerine flavour PHP-139220, Orange Juice flavour PHS-192439, saccharin and 2.213 g of sucrose.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

The sachet is a four layer laminate comprising of paper, polyethylene, aluminium and polyethylene, and is supplied in an outer cardboard carton, one sachet per carton.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes