Label: FOSFOMYCIN TROMETHAMINE- granules for oral powder

Fosfomycin Tromethamine Granules for Oral Solution 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:

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-gram dose of Fosfomycin Tromethamine, the mean (± 1 SD) maximum serum concentration (Cmax) achieved was 26.1 (± 9.1) mcg/mL within 2 hours. The oral bioavailability of fosfomycin is reduced to 30% under fed conditions. Following a single 3-gram oral dose of Fosfomycin Tromethamine with a high-fat meal, the mean Cmax achieved was 17.6 (± 4.4) mcg/mL within 4 hours. 

Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with Fosfomycin Tromethamine. Metoclopramide lowers the serum concentrations and urinary excretion of fosfomycin when coadministered with Fosfomycin Tromethamine. (See PRECAUTIONS, Drug Interactions.)

Distribution: The mean apparent steady-state volume of distribution (Vss) is 136.1 (±44.1) L following oral administration of Fosfomycin Tromethamine. 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 mcg 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 Fosfomycin Tromethamine, 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-gram dose of Fosfomycin Tromethamine 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) mcg/mL was attained within 2-4 hours after a single oral 3-gm dose of Fosfomycin Tromethamine under fasting conditions. The mean urinary concentration of fosfomycin was 10 mcg/mL in samples collected 72-84 hours following a single oral dose of Fosfomycin Tromethamine.

Following a 3-gram dose of Fosfomycin Tromethamine administered with a high fat meal, a mean urine fosfomycin concentration of 537 (± 252) mcg/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 mcg/mL were maintained for the same duration, 26 hours, indicating that Fosfomycin Tromethamine can be taken without regard to food.

Following oral administration of Fosfomycin Tromethamine, the mean half-life for elimination (t1/2) 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 t1/2 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 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.

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 mcg/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

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Fosfomycin Tromethamine 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. Fosfomycin Tromethamine is not indicated for the treatment of pyelonephritis or perinephric abscess.

If persistence or reappearance of bacteriuria occurs after treatment with Fosfomycin Tromethamine, other therapeutic agents should be selected. (See PRECAUTIONS and CLINICAL STUDIES sections.)

Fosfomycin Tromethamine is contraindicated in patients with known hypersensitivity to the drug.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Fosfomycin Tromethamine, 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.

In acute toxicology studies, oral administration of high doses of Fosfomycin Tromethamine up to 5 g/kg were well-tolerated in mice and rats, produced transient and minor incidences of watery stools 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 Fosfomycin Tromethamine 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.

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

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

Fosfomycin Tromethamine should be taken orally. Pour the entire contents of a single-dose sachet of Fosfomycin Tromethamine into 3 to 4 ounces of water (1/2 cup) and stir to dissolve. Do not use hot water. Fosfomycin Tromethamine should be taken immediately after dissolving in water.

Product: 50090-5826

NDC: 50090-5826-0 1 POWDER in a DOSE PACK / 1 in a CARTON

In controlled, double-blind studies of acute cystitis performed in the United States, a single-dose of Fosfomycin Tromethamine 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, 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.