FOSFOMYCIN TROMETHAMINE- granules for oral solution powder
XIROMED LLC
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Fosfomycin Tromethamine Granules for Oral Solution
Rx only
DESCRIPTION
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 C3H7O 4P.C4H11NO 3, and its chemical structure is as follows:
CLINICAL PHARMACOLOGY
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.
INDICATIONS AND USAGE
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.)
CONTRAINDICATIONS
Fosfomycin Tromethamine is contraindicated in patients with known hypersensitivity to
the drug.
WARNINGS
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.
PRECAUTIONS
General
Do not use more than one single dose of Fosfomycin Tromethamine to treat a single
episode of acute cystitis. Repeated daily doses of Fosfomycin Tromethamine 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 Fosfomycin Tromethamine can be taken with or without food.
That their symptoms should improve in two to three days after taking Fosfomycin
Tromethamine; 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.
Drug Interactions
Metoclopramide: When coadministered with Fosfomycin Tromethamine,
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 Fosfomycin Tromethamine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term carcinogenicity studies in rodents have not been conducted
because Fosfomycin Tromethamine is intended for single dose treatment in humans.
Fosfomycin Tromethamine 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. Fosfomycin Tromethamine did
not affect fertility or reproductive performance in male and female rats.
Pregnancy:
Teratogenic Effects
When administered intramuscularly as the sodium salt at a dose of 1 gram to
pregnant women, fosfomycin crosses the placental barrier. Fosfomycin
Tromethamine 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 Fosfomycin Tromethamine, 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 Fosfomycin Tromethamine 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.
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 listed below:
Drug-Related Adverse Events (%) in Fosfomycin and Comparator
Populations
Trimethoprim/
Adverse Fosfomycin Nitrofurantoin Ciprofoxacin
sulfamethoxazole
Events N=1233 N=374 N=455
N=428
Diarrhea 9.0 6.4 2.3 3.1
Vaginitis 5.5 5.3 4.7 6.3
Nausea 4.1 7.2 8.6 3.4
Headache 3.9 5.9 5.4 3.4
Dizziness 1.3 1.9 2.3 2.2
Asthenia 1.1 0.3 0.5 0.0
Dyspepsia 1.1 2.1 0.7 1.1
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%, 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
Fosfomycin Tromethamine therapy.
Post-marketing Experience:
Serious adverse events from the marketing experience with Fosfomycin Tromethamine
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 Fosfomycin
Tromethamine: anaphylaxis and hearing loss.
Laboratory Changes:
Significant laboratory changes reported in U.S. clinical trials of Fosfomycin
Tromethamine 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 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.
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 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.)
PREPARATION
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.
HOW SUPPLIED
Fosfomycin Tromethamine Granules for Oral Solution is available as a single-dose sachet
containing the equivalent of 3 grams of fosfomycin.
NDC
Single-dose sachet 70700-268-99
One unit carton 70700-268-94
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.
CLINICAL STUDIES
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.
Outcome
(based on
difference in
Treatment Clinical
Microbiologic microbiologic
Treatment Arm Duration Success
Eradication Rate eradication
(days) Rate
rates 5-11
days post
therapy)
5-11
Study
days
day
post
12-21
therapy
630/771 591/771 542/771
Fosfomycin 1
(82%) (77%) (70%)
Fosfomycin
219/222 219/222 213/222
Ciprofloxacin 7 inferior to
(98%) (98%) (96%)
ciprofloxacin
Fosfomycin
Trimethoprim/ 194/197 194/197 186/197 inferior to
10
sulfamethoxazole (98%) (98%) (94%) trimethoprim/
sulfamethoxazole
Fosfomycin
180/238 180/238 183/238
Nitrofurantoin 7 equivalent to
(76%) (76%) (77%)
nitrofurantoin
Trimethoprim/
Fosfomycin Ciprofloxacin Nitrofurantoin
sulfamethoxazole
Pathogen 3 gram 250 mg 100 mg
160 mg/800 mg
single dose bid x 7 days bid x 7 days
bid x 10 days
509/644 184/187 171/174 146/187
E. coli
(79%) (98%) (98%) (78%)
10/10 4/4 1/2
E. faecalis 0/0
(100%) (100%) (50%)
PRINCIPAL DISPLAY PANEL
NDC 70700-268-94
Fosfomycin Tromethamine Granules for Oral Solution
(equivalent to 3 grams of fosfomycin)
FOSFOMYCIN TROMETHAMINE
granules for oral solution powder
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70700-268
Route of Administration ORAL
Active Ingredient/Active Moiety
Basis of
Ingredient Name Strength
Strength
FOSFOMYCIN TROMETHAMINE (UNII: 7FXW6U30GY) (FOSFOMYCIN -
FOSFOMYCIN 3g
UNII:2N81MY12TE)
Inactive Ingredients
Ingredient Name Strength
TANGERINE (UNII: KH3E3096OO)
ORANGE (UNII: 5EVU04N5QU)
SACCHARIN (UNII: FST467XS7D)
SUCROSE (UNII: C151H8M554)
Packaging
Marketing Start Marketing End
# Item Code Package Description
Date Date
NDC:70700-268-
1 1 in 1 CARTON 10/06/2020
94
1 in 1 DOSE PACK; Type 0: Not a Combination
1
Product
NDC:70700-268- 1 in 1 PACKET; Type 0: Not a Combination
2 10/06/2020
99 Product
Marketing Information
Marketing Application Number or Monograph Marketing Start Marketing End
Category Citation Date Date
ANDA ANDA212548 10/06/2020
Labeler - XIROMED LLC (080228637)
Registrant - Xiromed Pharma Espana, S.L. (468835741)
Establishment
Name Address ID/FEI Business Operations
Laboratorios Licons a SAU 471409309 manufacture(70700-268)
Revised: 11/2020 XIROMED LLC
