MONUROL (fosfomycin tromethamine) sachet contains fosfomycin tromethamine, a synthetic, broad spectrum, bactericidal antibiotic for oral administration. It is available as a single-dose sachet which contains white granules consisting of 5.631 grams of fosfomycin tromethamine (equivalent to 3 grams of fosfomycin), and the following inactive ingredients: mandarin flavor, orange flavor, saccharin, and sucrose. The contents of the sachet must be dissolved in water. Fosfomycin tromethamine, a phosphonic acid derivative, is available as (1R,2S)-(1,2- epoxypropyl)phosphonic acid, compound with 2- amino-2-(hydroxymethyl)-1,3-propanediol (1:1). It is a white granular compound with a molecular weight of 259.2. Its empirical formula is C₃H₇O₄P·C₄H₁₁NO₃, and its chemical structure is as follows:

MONUROL is indicated only for the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis. MONUROL is not indicated for the treatment of pyelonephritis or perinephric abscess.

If persistence or reappearance of bacteriuria occurs after treatment with MONUROL, other therapeutic agents should be selected. (See PRECAUTIONS and Clinical Studies section.)

The recommended dosage for women 18 years of age and older for uncomplicated urinary tract infection (acute cystitis) is one sachet of MONUROL. MONUROL may be taken with or without food.

MONUROL should not be taken in its dry form. Always mix MONUROL with water before ingesting. (See PREPARATION section.)

PREPARATION

MONUROL should be taken orally. Pour the entire contents of a single-dose sachet of MONUROL into 3 to 4 ounces of water (½ cup) and stir to dissolve. Do not use hot water. MONUROL should be taken immediately after dissolving in water.

MONUROL is available as a single-dose sachet containing the equivalent of 3 grams of fosfomycin.

NDC # 0456-4300-08

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Keep this and all drugs out of the reach of children

Manufactured by: Zambon Switzerland Ltd. Division of Zambon Group, SpA, Via Industria 13, 6814 Cadempino, Switzerland. Made in Switzerland. Distributed by: Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045. Rev. 7/07. FDA rev date: 3/11/2008

Clinical Trials:

In clinical studies, drug related adverse events which were reported in greater than 1% of the fosfomycin- treated study population are listed below:

Drug-Related Adverse Events (%) in Fosfomycin and Comparator Populations

In clinical trials, the most frequently reported adverse events occurring in > 1% of the study population regardless of drug relationship were: diarrhea 10.4%, headache 10.3%, vaginitis 7.6%, nausea 5.2%, rhinitis 4.5%, back pain 3.0%, dysmenorrheal 2.6%, pharyngitis 2.5%, dizziness 2.3%, abdominal pain 2.2%, pain 2.2%, dyspepsia 1.8%, asthenia 1.7%, and rash 1.4%.

The following adverse events occurred in clinical trials at a rate of less than 1%, regardless of drug relationship:

abnormal stools, anorexia, constipation, dry mouth, dysuria, ear disorder, fever, flatulence, flu syndrome, hematuria, infection, insomnia, lymphadenopathy, menstrual disorder, migraine, myalgia, nervousness, paresthesia, pruritus, SGPT increased, skin disorder, somnolence, and vomiting.

One patient developed unilateral optic neuritis, an event considered possibly related to MONUROL therapy.

Post-marketing Experience:

Serious adverse events from the marketing experience with MONUROL outside of the United States have been rarely reported and include: angioedema, aplastic anemia, asthma (exacerbation), cholestatic jaundice, hepatic necrosis, and toxic megacolon.

Although causality has not been established, during post marketing surveillance, the following events have occurred in patients prescribed Monurol: anaphylaxis and hearing loss.

Laboratory Changes:

Significant laboratory changes reported in U.S. clinical trials of MONUROL without regard to drug relationship include: increased eosinophil count, increased or decreased WBC count, increased bilirubin, increased SGPT, increased SGOT, increased alkaline phosphatase, decreased hematocrit, decreased hemoglobin, increased and decreased platelet count. The changes were generally transient and were not clinically significant.

Metoclopramide: When coadministered with MONUROL, metoclopramide, a drug which increases gastrointestinal motility, lowers the serum concentration and urinary excretion of fosfomycin. Other drugs that increase gastrointestinal motility may produce similar effects.

Cimetidine: Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with MONUROL.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MONUROL, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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.

Urine specimens for culture and susceptibility testing should be obtained before and after completion of therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term carcinogenicity studies in rodents have not been conducted because MONUROL is intended for single dose treatment in humans. MONUROL was not mutagenic or genotoxic in the in vitro Ames' bacterial reversion test, in cultured human lymphocytes, in Chinese hamster V79 cells, and the in vivo mouse micronucleus assay. MONUROL did not affect fertility or reproductive performance in male and female rats.

Pregnancy: Teratogenic Effects

Pregnancy Category B

When administered intramuscularly as the sodium salt at a dose of 1 gm to pregnant women, fosfomycin crosses the placental barrier. MONUROL crosses the placental barrier of rats; it does not produce teratogenic effects in pregnant rats at dosages as high as 1000 mg/kg/day (approximately 9 and 1.4 times the human dose based on body weight and mg/m², respectively). When administered to pregnant female rabbits at dosages as high as 1000 mg/kg/day (approximately 9 and 2.7 times the human dose based on body weight and mg/m², respectively), fetotoxicities were observed. However, these toxicities were seen at maternally toxic doses and were considered to be due to the sensitivity of the rabbit to changes in the intestinal microflora resulting from the antibiotic administration. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether fosfomycin tromethamine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MONUROL, a decision should be made whether to discontinue nursing or to not administer the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in children age 12 years and under have not been established in adequate and well-controlled studies.

Geriatric Use: Clinical studies of Monurol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently

from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In acute toxicology studies, oral administration of high doses of MONUROL up to 5 gm/kg were well-tolerated in mice and rats, produced transient and minor incidences of watery stool in rabbits, and produced diarrhea with anorexia in dogs occurring 2-3 days after single dose administration. These doses represent 50-125 times the human therapeutic dose.

The following events have been observed in patients who have taken Monurol in overdose: vestibular loss, impaired hearing, metallic taste, and general decline in taste perception. In the event of overdosage, treatment should be symptomatic and supportive.

MONUROL is contraindicated in patients with known hypersensitivity to the drug.

Absorption: Fosfomycin tromethamine is rapidly absorbed following oral administration and converted to the free acid, fosfomycin. Absolute oral bioavailability under fasting conditions is 37%. After a single 3-gm dose of MONUROL, the mean (± 1 SD) maximum serum concentration (Cmax ) achieved was 26.1 (± 9.1) µg/mL within 2 hours. The oral bioavailability of fosfomycin is reduced to 30% under fed conditions. Following a single 3-gm oral dose of MONUROL with a high-fat meal, the mean Cmax achieved was 17.6 (± 4.4) µg/mL within 4 hours.

Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with MONUROL. Metoclopramide lowers the serum concentrations and urinary excretion of fosfomycin when coadministered with MONUROL. (See PRECAUTIONS: DRUG INTERACTIONS.)

Distribution: The mean apparent steady-state volume of distribution (Vss) is 136.1 (±44.1) L following oral administration of MONUROL. Fosfomycin is not bound to plasma proteins.

Fosfomycin is distributed to the kidneys, bladder wall, prostate, and seminal vesicles. Following a 50 mg/Kg dose of fosfomycin to patients undergoing urological surgery for bladder carcinoma, the mean concentration of fosfomycin in the bladder, taken at a distance from the neoplastic site, was 18.0 µg per gram of tissue at 3 hours after dosing. Fosfomycin has been shown to cross the placental barrier in animals and man.

Excretion: Fosfomycin is excreted unchanged in both urine and feces. Following oral administration of MONUROL, the mean total body clearance (CLTB) and mean renal clearance (CLR) of fosfomycin were 16.9 (± 3.5) L/hr and 6.3 (± 1.7) L/hr, respectively. Approximately 38% of a 3-gm dose of MONUROL is recovered from urine, and 18% is recovered from feces. Following intravenous administration, the mean CLTB and mean CLR of fosfomycin were 6.1 (± 1.0) L/hr and 5.5 (± 1.2) L/hr, respectively.

A mean urine fosfomycin concentration of 706 (± 466) µg/mL was attained within 2-4 hours after a single oral 3-gm dose of MONUROL under fasting conditions. The mean urinary concentration of fosfomycin was 10 µg/mL in samples collected 72-84 hours following a single oral dose of MONUROL.

Following a 3-gm dose of MONUROL administered with a high fat meal, a mean urine fosfomycin concentration of 537 (± 252) µg/mL was attained within 6-8 hours. Although the rate of urinary excretion of fosfomycin was reduced under fed conditions, the cumulative amount of fosfomycin excreted in the urine was the same, 1118 (± 201) mg (fed) vs. 1140 mg (± 238) (fasting). Further, urinary concentrations equal to or greater than 100 µg/mL were maintained for the same duration, 26 hours, indicating that MONUROL can be taken without regard to food.

Following oral administration of MONUROL, the mean half-life for elimination (t½) is 5.7 (± 2.8) hours.

Special Populations:

Geriatric: Based on limited data regarding 24-hour urinary drug concentrations, no differences in urinary excretion of fosfomycin have been observed in elderly subjects. No dosage adjustment is necessary in the elderly.

Gender: There are no gender differences in the Pharmacokinetics of fosfomycin.

Renal Insufficiency: In 5 anuric patients undergoing hemodialysis, the t½ of fosfomycin during hemodialysis was 40 hours. In patients with varying degrees of renal impairment (creatinine clearances varying from 54 mL/min to 7 mL/min), the t½ 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.

Microbiology

Fosfomycin (the active component of fosfomycin tromethamine) has in vitro activity against a broad range of gram-positive and gram-negative aerobic microorganisms which are associated with uncomplicated urinary tract infections. Fosfomycin is bactericidal in urine at therapeutic doses. The bactericidal action of fosfomycin is due to its inactivation of the enzyme enolpyruvyl transferase, thereby irreversibly blocking the condensation of uridine diphosphate- N-acetylglucosamine with p-enolpyruvate, one of the first steps in bacterial cell wall synthesis. It also reduces adherence of bacteria to uroepithelial cells.

There is generally no cross-resistance between fosfomycin and other classes of antibacterial agents such as beta-lactams and aminoglycosides.

Fosfomycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic gram-positive microorganisms

Enterococcus faecalis

Aerobic gram-negative microorganisms

Escherichia coli

The following in vitro data are available, but their clinical significance is unknown.

Fosfomycin exhibits in vitro minimum inhibitory concentrations (MIC's) of 64 µg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of fosfomycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials:

Aerobic gram-positive microorganisms

Enterococcus faecium

Aerobic gram-negative microorganisms

Citrobacter diversus
Citrobacter freundii
Enterobacter aerogenes
Klebsiella oxytoca
Klebsiella pneuomoniae
Proteus mirabilis
Proteus vulgaris
Serratia marcescens

Susceptibility Testing

Dilution Techniques:

Quantitative methods are used to determine minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized agar dilution method¹ or equivalent with standardized inoculum concentrations and standardized concentrations of fosfomycin tromethamine (in terms of fosfomycin base content) powder supplemented with 25 ^ig/mL of glucose-6- phosphate.BROTH DILUTION METHODS SHOULD NOT BE USED TO TEST SUSCEPTIBILITY TO FOSFOMYCIN. The MIC values obtained should be Interpreted according to the following criteria:

A report of "susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the urine.

A report of "intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "resistant" indicates that usually achievable concentrations of the antimicrobial compound in the urine are unlikely to be inhibitory and that other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard fosfomycin tromethamine powder should provide the following MIC values for agar dilution testing in media containing 25 µg/mL of glucose-6- phosphate [Broth dilution testing should not be performed].

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial agents. One such standardized procedure² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 200-ug fosfomycin and 50-ug of glucose-6-phosphate to test the susceptibility of microorganisms to fosfomycin.

Reports from the laboratory providing results of the standard single-disk susceptibility tests with disks containing 200 ug of fosfomycin and 50 ug of glucose- 6-phosphate should be interpreted according to the following criteria:

Interpretation should be stated as above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for fosfomycin.

As with standardized dilution techniques, diffusion methods require use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 200-ug fosfomycin disk with the 50-ug of glucose-6-phosphate should provide the following zone diameters in these laboratory quality control strains:

Clinical Studies

In controlled, double-blind studies of acute cystitis performed in the United States, a single-dose of MONUROL was compared to three other oral antibiotics (See table below). The study population consisted of patients with symptoms and signs of acute cystitis 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, and 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 these studies, the following clinical success (resolution of symptoms) and microbiologic eradication rates were obtained

REFERENCES

1.  National Committee for Clinical Laboratory Standards, Methods for Dilution. Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Third Edition; Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25 NCCLS, Villanova, PA, December, 1993.

2.  National Committee for Clinical Laboratory Standards, Performance Standard for Antimicrobial Disk Susceptibility Tests - Fifth Edition; Approved Standard NCCLS Document m²-A5, Vol. 13, No. 24 NCCLS, Villanova, PA, December, 1993.

Patients should be informed:

• That MONUROL (fosfomycin tromethamine) can be taken with or without food.
• That their symptoms should improve in two to three days after taking MONUROL; if not improved, the patient should contact her health care provider.
• Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FOSFOMYCIN TROMETHAMINE - ORAL

(foss-foh-MY-sin)

COMMON BRAND NAME(S): Monurol

USES: This medication is an antibiotic used to treat bladder infections (e.g., acute cystitis or lower urinary tract infections) in women. It works by stopping the growth of bacteria.

Fosfomycin should not be used to treat infections outside the bladder (e.g., kidney infections such as pyelonephritis or perinephric abscesses).

This antibiotic treats only bacterial infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or misuse of any antibiotic can lead to its decreased effectiveness.

HOW TO USE: Use 1 packet (sachet) only. This is a single-dose treatment. Always mix this drug with water. Pour the contents of 1 packet (sachet) into at least a half glass (4 ounces or 120 milliliters) of cold water and stir. Do not use warm or hot water. Drink the mixture immediately. This drug may be taken with or without food.

Symptoms should improve within 2 to 3 days after taking this drug. If symptoms persist or worsen, contact your doctor promptly.

SIDE EFFECTS: Diarrhea, nausea, stomach upset, headache, or dizziness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: vaginal discomfort, stomach/abdominal pain.

Tell your doctor immediately if any of these rare but very serious side effects occur: vision changes, dark urine, yellowing of the eyes/skin, unusual weakness.

This medication may rarely cause a severe intestinal condition (pseudomembranous colitis) due to a type of resistant bacteria. This condition may occur weeks to months after treatment has stopped. Tell your doctor immediately if you develop: persistent diarrhea, abdominal or stomach pain/cramping, blood/mucus in your stool.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking fosfomycin, tell your doctor or pharmacist if you are allergic to it; or to saccharin (an artificial sweetener); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease.

Do not use more than a single dose (1 packet or sachet) of this medication for each bladder infection. Using more packets will not make the drug work any better and may increase side effects.

If you develop symptoms of a kidney infection (such as pain in side/lower back area, fever, chills), contact your doctor immediately. You may need a different antibiotic to treat a kidney infection if one develops.

This drug may make you dizzy. Use caution while driving, using machinery, or taking part in any activity that requires alertness. Limit alcoholic beverages.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: metoclopramide.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center. Symptoms of overdose may include: hearing loss, metallic taste.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in that case.

Laboratory and/or medical tests (e.g., urine cultures) may be performed to monitor your progress. Consult your doctor for more details.

MISSED DOSE: Not applicable.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.