This document provides information on the composition, pharmacology, microbiology, and pharmacokinetics of the antibiotic Fosfomycin trometamol powder. It discusses how Fosfomycin is bactericidal by irreversibly blocking bacterial cell wall synthesis. Standardized susceptibility testing is performed using agar or broth dilution techniques to determine MIC values that are interpreted as susceptible, intermediate, or resistant.
This document provides information on the composition, pharmacology, microbiology, and pharmacokinetics of the antibiotic Fosfomycin trometamol powder. It discusses how Fosfomycin is bactericidal by irreversibly blocking bacterial cell wall synthesis. Standardized susceptibility testing is performed using agar or broth dilution techniques to determine MIC values that are interpreted as susceptible, intermediate, or resistant.
This document provides information on the composition, pharmacology, microbiology, and pharmacokinetics of the antibiotic Fosfomycin trometamol powder. It discusses how Fosfomycin is bactericidal by irreversibly blocking bacterial cell wall synthesis. Standardized susceptibility testing is performed using agar or broth dilution techniques to determine MIC values that are interpreted as susceptible, intermediate, or resistant.
trometamol) Dilution Techniques and 50 μg of glucose-6-phosphate to test
PDFSHARE Quantitative methods are used to the susceptibility of microorganisms to Prescribing Information determine MICs. These MICs provide fosfomycin. Overview estimates of the susceptibility of bacteria Reports from the laboratory providing Composition to antimicrobial compounds. One such results of the standard single-disk Each sachet contains: standardized procedure uses a standardized susceptibility tests with disks containing Fosfomycin trometamol BP equivalent to agar dilution method or equivalent with 200 μg of fosfomycin and 50 μg of Fosfomycin ….....3.0 gm standardized inoculum concentrations and glucose-6-phosphate should be interpreted Excipients ................................................... standardized concentrations of fosfomycin according to the following criteria: ...............................q.s. trometamol (in terms of fosfomycin base Zone Diameter content) powder supplemented with 25 Interpretation Dosage Form (mm) Powder μg/mL of glucose-6- phosphate. Broth ≥16 Susceptible (S) Pharmacology dilution methods should not be used to 13–15 Intermediate (I) Pharmacodynmics test susceptibility to fosfomycin. The MIC values obtained should be interpreted ≤12 Resistant (R) Mechanism of Action Fosfomycin trometamol is a synthetic, according to the following criteria: Interpretation should be stated as above for broad-spectrum, bactericidal antibiotic for MIC Interpretatio results using dilution techniques. oral administration. Fosfomycin (the active (μg/mL) n Interpretation involves correlation of the component of fosfomycin trometamol) has diameter obtained in the disk test with the Susceptible in vitro activity against a broad range of ≤64 MIC for fosfomycin. (S) gram-positive and gram-negative aerobic As with standardized dilution techniques, Intermediate diffusion methods require use of laboratory microorganisms which are associated with 128 (I) control microorganisms that are used to uncomplicated urinary tract infections. ≥256 Resistant (R) control the technical aspects of the Fosfomycin is bactericidal in urine at therapeutic doses. The bactericidal action A report of ‘susceptible’ indicates that the laboratory procedures. For the diffusion of fosfomycin is due to its inactivation of pathogen is likely to be inhibited by technique, the 200 μg fosfomycin disk the enzyme enolpyruvyl transferase, usually achievable concentrations of the with the 50 μg of glucose-6-phosphate thereby irreversibly blocking the antimicrobial compound in the urine. A should provide the following zone condensation of uridine diphosphate-N report of ‘intermediate’ indicates that the diameters in these laboratory quality acetylglucosamine with p-enolpyruvate, result should be considered equivocal, and, control strains: one of the first steps in bacterial cell wall if the microorganism is not fully Zone Diameter susceptible to alternative, clinically Microorganism synthesis. It also reduces adherence of (mm) bacteria to uroepithelial cells. feasible drugs, the test should be repeated. Escherichia coli ATCC This category provides a buffer zone that 22–30 There is generally no cross-resistance 25922 between fosfomycin and other classes of prevents small uncontrolled technical Staphylococcus aureus factors from causing major discrepancies 25–33 antibacterial agents such as beta-lactams ATCC 25923 and aminoglycosides. in interpretation. A report of 'resistant’ indicates that usually achievable Pharmacokinetics Microbiology Absorption: Fosfomycin trometamol is Fosfomycin has been shown to be active concentrations of the antimicrobial compound in the urine are unlikely to be rapidly absorbed following oral against most strains of the following administration and converted to the free microorganisms, both in vitro and in inhibitory and that other therapy should be selected. acid, fosfomycin. Absolute oral clinical infections: bioavailability under fasting conditions is Aerobic Gram-positive Microorganisms Standardized susceptibility test procedures require the use of laboratory control 37%. After a single 3 gm dose of Enterococcus faecalis fosfomycin trometamol, the mean (± 1 SD) Aerobic Gram-negative Microorganisms microorganisms. Standard fosfomycin trometamol powder should provide the maximum serum concentration (Cmax) Escherichia coli achieved was 26.1 (±9.1) μg/mL within 2 The following in vitro data are available, following MIC values for agar dilution testing in media containing 25 μg/mL of hours. The oral bioavailability of but their clinical significance is unknown. fosfomycin is reduced to 30% under fed Fosfomycin exhibits in vitro minimum glucose-6-phosphate. . conditions. Following a single 3 gm oral inhibitory concentrations (MICs) of 64 MIC Microorganism dose of fosfomycin trometamol with a μg/mL or less against most (≥90%) strains (μg/mL) high-fat meal, the mean Cmax achieved was of the following microorganisms; however, Enterococcus faecalis 17.6 (±4.4) μg/mL within 4 hours. 32–128 the safety and effectiveness of fosfomycin ATCC 29212 Cimetidine does not affect the in treating clinical infections due to these Escherichia coli ATCC pharmacokinetics of fosfomycin when co- 0.5–2 microorganisms has not been established 25922 administered with fosfomycin trometamol. in adequate and well-controlled clinical Pseudomonas aeruginosa Metoclopramide lowers the serum trials: 2–8 ATCC 27853 concentrations and urinary excretion of Aerobic Gram-positive Microorganisms Staphylococcus aureus fosfomycin when co-administered with Enterococcus faecium 0.5–4 fosfomycin. ATCC 29213 Aerobic Gram-negative Microorganisms Distribution: The mean apparent steady- Diffusion Techniques Citrobacter diversus state volume of distribution (Vss) is 136.1 Quantitative methods that require Citrobacter freundii (±44.1) L following oral administration of measurement of zone diameters also Enterobacter aerogenes fosfomycin trometamol. Fosfomycin is not provide reproducible estimates of the Klebsiella oxytoca bound to plasma proteins. susceptibility of bacteria to antimicrobial Klebsiella pneuomoniae Fosfomycin is distributed to the kidneys, agents. One such standardized procedure Proteus mirabilis bladder wall, prostate, and seminal requires the use of standardized inoculum Proteus vulgaris vesicles. Following a 50 mg/Kg dose of concentrations. This procedure uses paper Serratia marcescens fosfomycin to patients undergoing urological surgery for bladder carcinoma, significantly decreases the excretion of If CDAD is suspected or confirmed, the mean concentration of fosfomycin in fosfomycin. ongoing antibiotic use not directed against the bladder, taken at a distance from the Indications C. difficile may need to be discontinued. neoplastic site, was 18.0 μg per gram of FOSIROL is indicated only for the Appropriate fluid and electrolyte tissue at 3 hours after dosing. Fosfomycin treatment of uncomplicated urinary tract management, protein supplementation, has been shown to cross the placental infections (acute cystitis) in women due to antibiotic treatment of Clostridium barrier in animals and man. susceptible strains of Escherichia coli and difficile, and surgical evaluation should be Excretion: Fosfomycin is excreted Enterococcus faecalis. instituted as clinically indicated. unchanged in both urine and feces. FOSIROL is not indicated for the Drug Interactions Following oral administration of treatment of pyelonephritis or perinephric Metoclopramide: When co-administered fosfomycin trometamol, the mean total abscess. with fosfomycin trometamol, body clearance (CLTB) and mean renal If bacteriuria persists or reappears after metoclopramide, a drug which increases clearance (CLR) of fosfomycin were 16.9 treatment with FOSIROL, other gastrointestinal motility, lowers the serum (± 3.5) L/hr and 6.3 (± 1.7) L/hr, therapeutic agents should be selected. concentration and urinary excretion of respectively. Approximately 38% of a 3 Dosage and Administration fosfomycin. Other drugs that increase gm dose of fosfomycin trometamol is The recommended dosage for women, 18 gastrointestinal motility may produce recovered from urine, and 18% is years of age and older, for uncomplicated similar effects. recovered from feces. Following urinary tract infection (acute cystitis) is Cimetidine: Cimetidine does not affect the intravenous administration, the mean CLTB one sachet of FOSIROL. pharmacokinetics of fosfomycin when co- and mean CLR of fosfomycin were 6.1 FOSIROL may be taken with or without administered with fosfomycin trometamol. (±1.0) L/hr and 5.5 (±1.2) L/hr, food. Information for Patients respectively. FOSIROL should not be taken in its dry Patients should be informed: A mean urine fosfomycin concentration of form. Always mix FOSIROL with water That FOSIROL can be taken 706 (± 466) μg/mL was attained within 2-4 before ingesting. with or without food. hours after a single oral 3 gm dose of Method of Preparation That their symptoms should fosfomycin trometamol under fasting FOSIROL should be taken orally. Pour improve in 2–3 days after taking conditions. The mean urinary the entire contents of a single-dose sachet FOSIROL; if not improved, the patient concentration of fosfomycin was 10 μg/mL of FOSIROL into a glass of water (90-120 should contact her health care provider. in samples collected at 72–84 hours ml) and stir to dissolve. Do not use hot Diarrhea is a common problem following a single oral dose of fosfomycin water. FOSIROL should be taken caused by antibiotics which usually trometamol. immediately after dissolving in water. ends when the antibiotic is Following a 3-gm dose of fosfomycin Contraindications discontinued. Sometimes after starting trometamol administered with a high fat FOSIROL is contraindicated in patients treatment with antibiotics, patients can meal, a mean urine fosfomycin with known hypersensitivity to the drug. develop watery and bloody stools (with concentration of 537 (± 252) μg/mL was Warnings and Precautions or without stomach cramps and fever) attained within 6-8 hours. Although the General even as late as 2 or more months after rate of urinary excretion of fosfomycin Do not use more than one single dose of having taken the last dose of the was reduced under fed conditions, the FOSIROL to treat a single episode of antibiotic. If this occurs, patients cumulative amount of fosfomycin excreted acute cystitis. Repeated daily doses of should contact their physician as soon in the urine was the same, i.e 1,118 (± 201) fosfomycin trometamol did not improve as possible. mg (fed) vs. 1,140 mg (± 238) (fasting). the clinical success or microbiological Renal Impairment Further, urinary concentrations equal to or eradication rates compared to single dose Dosage adjustment is not necessary. greater than 100 µg/mL were maintained therapy, but did increase the incidence of Hepatic Impairment for the same duration (26 hours), adverse events. Urine specimens for No specific dosage recommendations can indicating that fosfomycin trometamol can culture and susceptibility testing should be be made. be taken without regard to food. obtained before and after completion of Pregnancy Following oral administration of therapy. Pregnancy Category B fosfomycin trometamol, the mean half-life Clostridium difficile-associated diarrhoea When administered intramuscularly as the for elimination (t1/2) is 5.7 (± 2.8) hours. (CDAD) has been reported with the use of sodium salt at a dose of 1 gm to pregnant Pharmacokinetics in Special Populations nearly all antibacterial agents, including women, fosfomycin crosses the placental Geriatric: Based on limited data regarding fosfomycin trometamol, and may range in barrier. There are, however, no adequate 24-hour urinary drug concentrations, no severity from mild diarrhoea to fatal and well-controlled studies in pregnant differences in urinary excretion of colitis. Treatment with antibacterial agents women. Because animal reproduction fosfomycin have been observed in elderly alters the normal flora of the colon, leading studies are not always predictive of human subjects. No dosage adjustment is to overgrowth of Clostridium difficile. response, this drug should be used during necessary in the elderly. Clostridium difficile produces toxins A and pregnancy only if clearly needed. Gender: There are no gender differences in B, which contribute to the development of Lactation the pharmacokinetics of fosfomycin. CDAD. Hypertoxin-producing strains of It is not known whether fosfomycin Renal Impairment: In five anuric patients Clostridium difficile cause increased trometamol is excreted in human milk. undergoing hemodialysis, the t1/2 of morbidity and mortality, as these Because many drugs are excreted in human fosfomycin during hemodialysis was 40 infections can be refractory to milk and because of the potential for hours. In patients with varying degrees of antimicrobial therapy and may require a serious adverse reactions in nursing infants renal impairment (creatinine clearances colectomy. CDAD must be considered in from fosfomycin trometamol, a decision varying from 54 mL/min to 7 mL/min), the all patients who present with diarrhoea should be made whether to discontinue t1/2 of fosfomycin increased from 11 hours following antibiotic use. Careful medical nursing or to not administer the drug, to 50 hours. The percent of fosfomycin history is necessary since CDAD has been taking into account the importance of the recovered in urine decreased from 32% to reported to occur over 2 months after the drug to the mother. 11% indicating that renal impairment administration of antibacterial agents. Pediatric Use Safety and effectiveness in children age 12 One patient developed unilateral optic years and under have not been established neuritis, an event considered possibly in adequate and well-controlled studies. related to fosfomycin trometamol therapy. Geriatric Use Postmarketing Experience Clinical studies of fosfomycin trometamol Serious adverse events from the marketing did not include sufficient numbers of experience with fosfomycin trometamol subjects aged 65 and over to determine outside of the United States have been whether they respond differently from rarely reported and include the following: younger subjects. Other reported clinical angio-oedema, aplastic anemia, asthma experience has not identified differences in (exacerbation), cholestatic jaundice, responses between the elderly and younger hepatic necrosis, and toxic megacolon. patients. In general, dose selection for an Although causality has not been elderly patient should be cautious, usually established, during post marketing starting at the low end of the dosing range, surveillance, the following events have reflecting the greater frequency of occurred in patients prescribed fosfomycin decreased hepatic, renal, or cardiac trometamol: anaphylaxis and hearing loss. function, and of concomitant disease or Laboratory Changes other drug therapy. Significant laboratory changes reported in Undesirable Effects U.S. clinical trials of fosfomycin Clinical Trials trometamol without regard to drug In clinical studies, drug related adverse relationship include: increased eosinophil events which were reported in greater than count, increased or decreased WBC count, 1% of the fosfomycin trometamol treated increased bilirubin, increased SGPT, study population are listed below: increased SGOT, increased alkaline Drug-Related Adverse Events (%) in phosphatase, decreased hematocrit, Fosfomycin Trometamol and decreased hemoglobin, increased and Comparator Populations decreased platelet count. The changes were Fosfo generally transient and were not clinically Trimetho significant. Adve mycin Nitrofu Ciprofl prim/ Overdosage rse Trome rantoin oxacin Sulfamet The following events have been observed Even tamol hoxazole in patients who have taken fosfomycin ts N=123 N=374 N=455 N=428 trometamol in overdose: vestibular loss, 3 Diarr impaired hearing, metallic taste, and 9.0 6.4 2.3 3.1 general decline in taste perception. In the hoea event of overdosage, treatment should be Vagi 5.5 5.3 4.7 6.3 symptomatic and supportive. nitis Storage and Handling Instruction Naus Store below 25°C. 4.1 7.2 8.6 3.4 ea Packaging Information Head FOSIROL................. Sachet of 3 gm each 3.9 5.9 5.4 3.4 ache Last Updated: Dec 2013 Dizzi Last Reviewed: May 2016 1.3 1.9 2.3 2.2 ness Table of Content Asth Composition 1.1 0.3 0.5 0.0 enia Dosage Form Dysp Pharmacology 1.1 2.1 0.7 1.1 epsia Indications In clinical trials, the most frequently Dosage and Administration reported adverse events occurring in >1% Contraindications of the study population regardless of drug Warnings and Precautions relationship were as follows: diarrhoea Undesirable Effects (10.4%), headache (10.3%), vaginitis Overdosage (7.6%), nausea (5.2%), rhinitis (4.5%), Storage and Handling Instruction back pain (3.0%), dysmenorrheal (2.6%), Packaging Information pharyngitis (2.5%), dizziness (2.3%), Featured Content abdominal pain (2.2%), pain (2.2%), Intracameral Moxifloxacin dyspepsia (1.8%), asthenia (1.7%), and Safe in Children for rash (1.4%). Reducing... The following adverse events occurred in Infants with PPHN Burdened clinical trials at a rate of less than 1%, with Increased Morbidity regardless of drug relationship: abnormal and... stools, anorexia, constipation, dry mouth, dysuria, ear disorder, fever, flatulence, flu Migraine and Elevated IOP syndrome, hematuria, infection, insomnia, Increase the Risk of Low lymphadenopathy, menstrual disorder, Ocular... migraine, myalgia, nervousness, paresthesia, pruritus, SGPT increased, skin disorder, somnolence, and vomiting.