ADVERSE REACTIONS SECTION.

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 Adverse Events Fosfomycin N=1233 Nitrofurantoin N= 374 Trimethoprim/ sulfamethoxazole N=428 Ciprofloxacin N=455 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 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.

CLINICAL PHARMACOLOGY SECTION.

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 single 3-gram dose of fosfomycin tromethamine, the mean (+- SD) maximum serum concentration (Cmax) achieved was 26.1 (+- 9.1) mcg/mL within hours. The oral bioavailability of fosfomycin is reduced to 30% under fed conditions. Following single 3-gram oral dose of fosfomycin tromethamine with high-fat meal, the mean Cmax achieved was 17.6 (+- 4.4) mcg/mL within 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) 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 50 mg/kg dose of fosfomycin to patients undergoing urological surgery for bladder carcinoma, the mean concentration of fosfomycin in the bladder, taken at distance from the neoplastic site, was 18.0 mcg per gram of tissue at 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 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.. mean urine fosfomycin concentration of 706 (+- 466) mcg/mL was attained within 2-4 hours after 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 single oral dose of fosfomycin tromethamine.Following 3-gram dose of fosfomycin tromethamine administered with high fat meal, 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 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 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 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 microorganismsEnterococcus faecalisAerobic gram-negative microorganisms Escherichia coliThe following in vitro data are available, but their clinical significance is unknown. Fosfomycin exhibits in vitro minimum inhibitory concentrations (MICs) 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 faeciumAerobic gram-negative microorganismsCitrobacter diversusCitrobacter freundiiEnterobacter aerogenesKlebsiella oxytocaKlebsiella pneuomoniaeProteus mirabilisProteus vulgaris Serratia marcescensSUSCEPTIBILITY TESTINGFor 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.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. In controlled, double-blind studies of acute cystitis performed in the United States, 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 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 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. Treatment Arm Treatment Duration (days) Microbiologic Eradication Rate Clinical Success Rate Outcome (based on difference in microbiologic eradication rates 5-11 days post therapy) 5-11 days post therapy Study day 12-21 Fosfomycin 630/771 (82%) 591/771 (77%) 542/771 (70%) Ciprofloxacin 219/222 (98%) 219/222 (98%) 213/222 (96%) Fosfomycin inferior to ciprofloxacin Trimethoprim/ sulfamethoxazole 10 194/197 (98%) 194/197 (98%) 186/197 (94%) Fosfomycin inferior to trimethoprim/ sulfamethoxazole Nitrofurantoin 180/238 (76%) 180/238 (76%) 183/238 (77%) Fosfomycin equivalent to nitrofurantoin Pathogen Fosfomycin gram single dose Ciprofloxacin 250 mg bid 7 days Trimethoprim/ sulfamethoxazole 160 mg/800 mg bid 10 days Nitrofurantoin 100 mg bid 7 daysE. coli 509/644 (79%) 184/187 (98%) 171/174 (98%) 146/187 (78%) E. faecalis 10/10 (100%) 0/0 4/4 (100%) 1/2 (50%) Manufactured by:Cipla Ltd., Kurkumbh,India Manufactured for: Cipla USA, Inc., 10 Independence Boulevard, Suite 300Warren, NJ 07059 Revised: 2/2020.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients should be informed:That fosfomycin tromethamine granules for oral solution can be taken with or without food.That their symptoms should improve in two to three days after taking fosfomycin tromethamine granules for oral solution; if not improved, the patient should contact her health care provider.Diarrhea is 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.. That fosfomycin tromethamine granules for oral solution can be taken with or without food.. That their symptoms should improve in two to three days after taking fosfomycin tromethamine granules for oral solution; if not improved, the patient should contact her health care provider.. Diarrhea is 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.

MICROBIOLOGY SECTION.

Microbiology. Fosfomycin (the active component of fosfomycin tromethamine) has in vitro activity against 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 microorganismsEnterococcus faecalisAerobic gram-negative microorganisms Escherichia coliThe following in vitro data are available, but their clinical significance is unknown. Fosfomycin exhibits in vitro minimum inhibitory concentrations (MICs) 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 faeciumAerobic gram-negative microorganismsCitrobacter diversusCitrobacter freundiiEnterobacter aerogenesKlebsiella oxytocaKlebsiella pneuomoniaeProteus mirabilisProteus vulgaris Serratia marcescensSUSCEPTIBILITY TESTINGFor 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.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Do not use more than one single dose of fosfomycin tromethamine granules for oral solution to treat 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 granules for oral solution can be taken with or without food.That their symptoms should improve in two to three days after taking fosfomycin tromethamine granules for oral solution; if not improved, the patient should contact her health care provider.Diarrhea is 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.. That fosfomycin tromethamine granules for oral solution can be taken with or without food.. That their symptoms should improve in two to three days after taking fosfomycin tromethamine granules for oral solution; if not improved, the patient should contact her health care provider.. Diarrhea is 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, 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 dose of 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 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 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, 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.

WARNINGS SECTION.

WARNINGS. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including fosfomycin tromethamine granules for oral solution, 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 and 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.