Fosfomycin Tromethamine 3 g Granule, For Solution, 1 granule — NDC 81033-024-11 (Billing 81033-0024-11)

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.

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 Ciprofoxacin N=455 Diarrhea 9.0 6.4 2.3

3.1Vaginitis 5.5 5.3 4.7

6.3Nausea 4.1 7.2 8.6

3.4Headache 3.9 5.9 5.4

3.4Dizziness 1.3 1.9 2.3

2.2Asthenia 1.1 0.3 0.5

0.0Dyspepsia 1.1 2.1 0.7

1.1In clinical trials, the most frequently reported adverse events occurring in greater than 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.

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.

PRECAUTIONS GENERAL PRECAUTIONS Do not use more than one single dose of fosfomycin tromethamine granules for oral solution to treat a single episode of acute cystitis. Repeated daily doses of fosfomycin tromethamine granules for oral solution 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 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/m 2 , 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/m 2 , 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.

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