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MONUROL®
[mon' ur ol]
(fosfomycin tromethamine)
SACHET

Rev. 5/04

RMC 237

Rxonly

DESCRIPTION

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 spans 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:

CLINICAL PHARMACOLOGY

Special Populations:

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 penolpyruvate, 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:

SUSCEPTIBILITY TESTING

INDICATIONS AND USAGE

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.)

CONTRAINDICATIONS

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

PRECAUTIONS

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.

Information for Patients

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.

Drug Interactions

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

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.

ADVERSE REACTIONS

Clinical Trials:

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

Drug-Related Adverse Events (%) in Fosfomycin and Comparator Populations
Adverse EventsFosfomycin
N=1233
Nitrofurantoin
N=374
Trimethoprim/ sulfamethoxazole
N=428
Ciprofloxacin
N=455
Diarrhea9.06.42.33.1
Vaginitis5.55.34.76.3
Nausea4.17.28.63.4
Headache3.95.95.43.4
Dizziness1.31.92.32.2
Asthenia1.10.30.50.0
Dyspepsia1.12.10.71.1

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%, dysmenorrhea 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 postmarketing 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.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

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 spans of a single-dose sachet of MONUROL into 3 to 4 ounces of water (1/2 cup) and stir to dissolve. Do not use hot water. MONUROL should be taken immediately after dissolving in water.

HOW SUPPLIED

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

REFERENCES

  • 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.
  • 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.

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.

Treatment ArmTreatment Duration (days)Microbiologic Eradication RateClinical Success RateOutcome (based on difference in microbiologic eradication rates 5-11 days post therapy)
5-11 days post therapyStudy day 12-21
Fosfomycin1630/771 (82%)591/771 (77%)542/771 (70%)
Ciprofloxacin7219/222(98%)219/222 (98%)213/222 (96%)Fosfomycin inferior to ciprofloxacin
Trimethoprim/
sulfamethoxazole
10194/197(98%)194/197(98%)186/197(94%)Fosfomycin inferior to trimethoprim/ sulfamethoxazole
Nitrofurantoin7180/238(76%)180/238(76%)183/238(77%)Fosfomycin equivalent to nitrofurantoin
PathogenFosfomycin 3 gm single doseCiprofloxacin 250 mg bid x 7dTrimethoprim/sulfamethoxazole 160 mg/ 800 mg bid x 10 dNitrofurantoin 100mg bid x 7d
E. coli509/644 (79%)184/187 (98%)171/174 (98%)146/187 (78%)
E. faecalis10/10 (100%)0/04/4 (100%)1/2 (50%)
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