Approved on.
Date of revision.
Fosfomycin Aminotriol Disodium Instructions
Please read the instructions carefully and use under the guidance of your physician
[Drug Name].
Generic name: Fosfomycin aminotriol
English name: Fosfomycin Trometamol Powder
Hanyu Pinyin: Linmeisu Andingsanchun San
[Ingredient
The main ingredient of this product is phosphomycin trometamol.
Chemical name: (2-Amino-2-hydroxymethyl-1,3-propanediol) (2R-cis) – (3-methyloxirane) monophosphate
Chemical structure formula.
Molecular formula: C7H18NO7P
Molecular weight: 259.20
[Properties
This product is a powder.
[Indications
1. This product is used for the treatment of the following infections caused by sensitive Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, Citrobacter spp, Enterobacter spp, and Aspergillus chimaera.
1) Acute simple urinary tract infections.
2) Asymptomatic bacteriuria.
2. This product is used to prevent infections caused by surgical procedures or diagnostic procedures in the lower urinary tract (e.g., transurethral resection associated with urethra).
[Specification
3g (3 million units) (based on C3H7O4P)
[Dosage].
1. Dosage
1) Adults and adolescents weighing 50 kg or more.
Treatment.
Single dose treatment, 1 bottle per course (3g active ingredient).
Prevention.
For the prevention of infections caused by surgical procedures or diagnostic procedures in the lower urinary tract, treatment usually consists of 2 times the dose of this product, with an initial dose of 1 vial (3 g active ingredient) administered orally 3 hours before surgery and a second dose of 1 vial (3 g active ingredient) administered orally 24 hours after surgery.
2) Adults and adolescents weighing up to 50 kg
Treatment.
Single-dose therapy with 2/3 vials (2 g active ingredient) per course.
Prevention.
Approximately 2/3 vials (2 g active ingredient) each orally 3 hours preoperatively and 24 hours postoperatively.
3) Children
Experience with pediatric use is limited, and because the dose is not appropriate for children under 12 years of age, this product is not recommended for use in children in this age group.
2. Usage
This product should be taken on an empty stomach, 2-3 hours before or after a meal, preferably after emptying the bladder during the evening.
Take an appropriate amount of this product, such as each bottle (3g active ingredient) in 50-70ml of water, stir until dissolved and then take immediately. Hot water should not be used.
This product should not be taken directly by mouth without dissolving.
[Adverse Reactions
Adverse reactions that have occurred following the use of phosphomycin aminotriol in different countries or regions vary. The following adverse reactions have been reported in the literature.
1. United States
1) Clinical trials
Fosfomycin-related adverse reactions that accounted for a frequency of >1% of all adverse events in clinical studies are shown in the following table.
Phosphomycin and control drug populations for drug-related adverse events (%)
Adverse eventsPhosphomycin
N=1233furantoin
N=374Methoprene /sulfamethoxazole
N=428Ciprofloxacin
N=455Diarrhea9.06.42.33.1Vaginitis5.55.34.76.3 Disgusting4.17.28.63.4Headache3.95.95.43.4Dizziness1.31.92.32.2Lackluster1.10.30.50.0Indigestion1.12.10.71.1In the study population of the clinical trial, the adverse events that were reported to occur with a frequency > 1% ( drug-related unknown) were: diarrhea (10.4%), headache (10.3%), vaginitis (7.6%), nausea (5.2%), rhinitis (4.5%), back pain (3.0%), dysmenorrhea (2.6%), pharyngitis (2.5%), dizziness (2.3%), abdominal pain (2.2%), pain (2.2%), dyspepsia (1.8%), malaise (1.7% ) and skin rash (1.4%).
The following adverse reactions occurred in clinical trials<1%(drug-related unknown): stool abnormalities, anorexia, constipation, dry mouth, dysuria, ear disease, fever, gastrointestinal distention, influenza syndrome, hematuria, infection, insomnia, lymphadenopathy, menstrual disorders, migraine, myalgia, neuroticism, sensory abnormalities, pruritus, elevated SGPT, skin disorders, drowsiness, and vomiting.
One patient developed unilateral optic neuritis, an event that may have been associated with fosfomycin aminotriol.
Laboratory
Important laboratory changes (of unknown drug relevance) have been reported in clinical trials conducted in the United States, including: elevated eosinophil counts, elevated or decreased WBC counts, elevated bilirubin, elevated SGPT, elevated SGOT, elevated alkaline phosphatase, decreased erythrocyte pressure product, decreased hemoglobin, and elevated and decreased platelet counts. These changes are usually transient and not clinically significant.
2) Post-marketing
Serious postmarketing adverse reactions to phosphomycin aminotriol that have been reported rarely outside the United States include: angioedema, aplastic anemia, asthma (worsening), cholestatic jaundice, hepatic necrosis, and toxic megacolon.
The following events occurred during postmarketing surveillance in patients taking fosfomycin aminotriol, but causality has not been established: allergic reactions and hearing loss.
2. Switzerland
The most common adverse reactions following single-dose administration of phosphomycin aminotriol were gastrointestinal reactions, mainly diarrhea. These adverse reactions usually resolve on their own and do not require specific corresponding treatment.
Adverse reactions reported during clinical trials and post-marketing for fosfomycin aminotriol are shown in the table below.
System organ classificationAdverse effectsCommon
( ≥1/100 to <1/10)Eventually
(≥1/1000 to<1/100 )Rare
(≥1/10,000 to <1/1000 )unknownInfections and parasitic infectionsVulvovaginitis Immune System Allergic reactions, including anaphylaxis and hypersensitivity reactionsNervous SystemHeadache, dizzinessFeeling abnormal Heart Tachycardia Breathing, thorax and mediastinum AsthmaGastrointestinal tract Diarrhea, nausea, indigestion Vomiting, abdominal pain Antibiotic-associated enteritisskin and subcutaneous tissue Rashes, hives, pruritus angioedemaGeneral disease and injection site reactions Lackluster Vessels Vessels Low blood pressure3, China
Since the launch of fosfomycin aminotriol in China, no Adverse reactions have not been reported.
[Contraindications
It is contraindicated in patients who are hypersensitive to the active ingredient fosfomycin or any of the excipients, in those with renal insufficiency (creatinine clearance Ccr <10ml/min) and in patients on hemodialysis.
[Precautions].
1. Warnings
Clostridium difficile produces toxins A and B, which contribute to CDAD. The production of virulins by C. difficile strains leads to increased morbidity and mortality, and because these infections are difficult to cure with antimicrobial therapy, colonic resection may be required. CDAD must be considered in patients who develop diarrhea after antibiotic use. a detailed history is necessary because CDAD has been reported to occur within 2 months after administration of antimicrobials.
If CDAD is suspected or identified, ongoing antibiotics that do not directly target C. difficile need to be discontinued. Appropriate fluid and electrolyte regulation, protein supplementation, antibiotic therapy targeting C. difficile, and surgical evaluation based on clinical indications should be given for C. difficile.
Antibiotic-associated diarrhea has been reported in association with the use of almost all broad-spectrum antibiotics, including fosfomycin aminotriol, and can range in severity from mild diarrhea to lethal enterocolitis. Diarrhea, especially severe, persistent and/or hemorrhagic diarrhea, occurring during or after treatment with this product, may be a symptom of Clostridium difficile-associated diarrheal disease (CDAD). Therefore, special attention should be paid to the fact that this diagnosis should be considered when severe diarrhea occurs during or after the use of this product. If CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated immediately and drugs that inhibit bowel movements should be contraindicated.
2) Metabolic reactions
Pathological reactions (including hypersensitivity reactions and anaphylaxis) may occur during fosfomycin therapy and may be life-threatening. If such reactions occur, phosphomycin should not be given again and appropriate medication is needed.
2. General Precautions
For a single episode of acute cystitis, single-dose treatment with this product should not be used more than once. Repeated daily administration of this product does not improve clinical efficacy or microbial eradication rates compared with single treatment, but does increase the incidence of adverse events. Urine samples should be obtained, cultured, and tested for drug sensitivity before and after completion of treatment.
Meals can interfere with the absorption of the active compounds of this product, resulting in a slight decrease in blood and urine concentrations. Therefore, this product must be taken on an empty stomach, 2-3 hours before or after a meal, preferably in the evening after the bladder has been emptied.
In renal insufficiency: If creatinine clearance is greater than 10 ml/min, urinary drug concentrations of fosfomycin may remain effective for 48 hours.
Because this product can cause vertigo, it may affect some patients driving and operating machinery.
This product should be kept out of the reach of children. Do not use products that are marked on the box as expired.
3. Patient information
Patients should be informed that.
Their symptoms should improve within 2 to 3 days of taking this product, and if they do not, they should contact their healthcare provider.
Diarrhea is a common problem caused by antibiotics and stops when the antibiotic is stopped. Sometimes watery stools and bloody stools (with or without stomach cramps and fever) occur in patients after starting antibiotic therapy, even up to 2 months after the last antibiotic was given. If diarrhea occurs, patients should contact their doctor as soon as possible.
[For pregnant and breastfeeding women
Pregnancy.
Pregnancy Classification B
Fosfomycin penetrates the placental barrier in pregnant women by intramuscular injection of a dose of sodium salt formulated to 1 gm. Phosphomycin aminotriol penetrated the placental barrier in rats, but doses up to 1000 mg/kg/day (approximately 9 and 1.4 times the human dose based on body weight and mg/m2, respectively) did not produce teratogenic effects in pregnant rats. No fetal toxicity was observed in pregnant female rabbits given doses up to 1000 mg/kg/day (approximately 9 and 2.7 times the human dose based on body weight and mg/m2, respectively). However, these toxicities were observed at maternal toxic doses and are thought to be possibly due to sensitivity to changes in intestinal flora resulting from antibiotic administration to rabbits. However, no appropriate and adequately controlled studies have been conducted in pregnant females. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
At present, it is not considered appropriate to use single-dose antimicrobial therapy for urinary tract infections in women in pregnancy.
Only limited safety data are available for fosfomycin in pregnant women, and these data do not indicate teratogenicity or fetal/neonatal toxicity.
Fosfomycin should be given with caution to women during pregnancy.
Lactation.
Because phosphomycin can pass into breast milk after a single oral dose. Therefore, treatment with this product should not be used during lactation, except when necessary.
Renatal Period.
Animal studies have shown no effect on fertility. Relevant data in humans are lacking.
[Pediatric Dosage].
There is a lack of sufficiently well-designed clinical trials to validate the efficacy and safety of fosfomycin aminotriol in children 12 years of age and younger.
Experience with pediatric use is limited, and because the dose is not appropriate for use in children younger than 12 years of age, this product is not recommended for use in children in this age group. .
[Geriatric Use
The number of subjects aged 65 years and older included in clinical studies of fosfomycin aminotriol was not sufficient to determine whether they responded differently than younger subjects. Other clinical experiences do not indicate a difference in response between older and younger subjects. In general, doses in older patients should be carefully selected, usually starting at the smallest dose in the dose range, and when combined with other drug therapy, more consideration should be given to the reduced hepatic, renal, or cardiac function and coexisting disease in older patients. .
[Drug Interactions].
Metoclopramide: When given in combination with fosfomycin aminotriol, metoclopramide increases gastrointestinal motility and decreases serum concentrations and urinary excretion of fosfomycin. Other drugs that increase gastrointestinal motility may have similar effects.
Cimetidine: Cimetidine does not affect the pharmacokinetics of fosfomycin when given in combination with fosfomycin aminotriol.
On specific issues involving changes in INR (international normalized ratio), a large number of cases have been reported showing increased vitamin K antagonist activity in patients treated with antibiotics. Risk factors include severe infection or inflammation, as well as advanced age and poor general health status. In such cases, it is difficult to determine whether the INR changes are due to an infectious disease or to its treatment. However, other classes of antibiotics, particularly fluoroquinolones, macrolides, cytokinins, cotrimoxazole, and certain cephalosporins are more likely to contribute to this problem.
[Drug overdose].
In acute toxicity studies, high doses of fosfomycin aminotriol given orally at 5 gm/kg were well tolerated in mice and rats, produced transient watery stools in rabbits with minimal incidence, and produced diarrhea and anorexia in dogs, occurring 2-3 days after a single dose. These doses are 50-125 times the human therapeutic dose.
Data on oral overdose of fosfomycin are limited.
The following symptoms have been observed with overdose of phosphomycin aminotriol: loss of vestibular function, impaired hearing, metallic taste and diminished sense of taste.
Extra-gastric overdose of fosfomycin has been reported to be associated with hypotension, somnolence, electrolyte disturbances, thrombocytopenia, and the appearance of hypoprothrombinemia.
Symptomatic and supportive therapy should be given. Those who overdose should drink plenty of water to accelerate excretion of the product from the urine.
[Pharmacology and Toxicology
Pharmacology.
Fosfomycin (the active component of fosfomycin aminotriol) has shown broad activity against Gram-positive and Gram-negative aerobic microorganisms associated with simple urinary tract infections in in vitro tests. Phosphomycin in urine at therapeutic doses has a bactericidal effect. The bactericidal effect of phosphomycin lies in the inactivation of enolpyruvate transferase, thus irreversibly blocking the condensation of uridine diphosphate-N-acetylglucosamine with phosphoenolpyruvate, a step that is the first step in bacterial cell wall synthesis. Phosphomycin also reduces bacterial adhesion to urinary epithelial cells.
Typically, phosphomycin is not cross-resistant to other classes of antimicrobials, such as beta-lactams and aminoglycosides.
Fosfomycin has been shown to be active in in vitro assays and in clinical infections against most strains of the following microorganisms.
aerobic gram-positive bacteria
Enterococcus faecalis
Aerobic Gram-negative bacteria
Escherichia coli
In addition, the following in vitro test data were obtained, but their clinical significance is unclear.
Minimum inhibitory concentrations (MICs) of phosphomycin in in vitro trials were ≤64 μg/mL for most (≥90%) strains of the following microorganisms, but the safety and efficacy of phosphomycin in treating clinical infections caused by these microorganisms has not been established in adequate and well-controlled clinical trials.
Oxigenic Gram-positive microorganisms
Enterococcus faecalis
Aerobic Gram-negative microorganisms
Bacillus heterotrophicus
Flaudy Citrobacter
Enterobacter aerogenes
Klebsiella acidophilus
Klebsiella pneumoniae
Chlamydomonas oddis
Pseudomonas aeruginosa
Salmonella mucilaginosa
Dilution method.
The minimum inhibitory concentration (MIC) is determined using a quantitative method. the MIC gives an estimate of the susceptibility of the bacteria to the antimicrobial compound. This standard method uses a standard agar dilution method1 or equivalent, a standard inoculum concentration, and a standard concentration of phosphomycin aminotriol (based on phosphomycin base content) powder supplemented with 25 μg/mL glucose 6-phosphate. The broth dilution method should not be used for phosphomycin drug sensitivity testing. Interpret the MIC values obtained according to the following criteria.
MIC (μg/mL)Explanation≤ 64Sensitive(S)128Intermediary (I)≥ 256 Resistant (R)”Sensitive” reports suggest that the anti-microbial concentrations normally achieved in urine are likely to inhibit the pathogen. “Intermediary” reports suggest that the results are inconclusive and that the test should be repeated if the microorganism is not fully sensitive to an alternative, clinically feasible drug. This category provides a buffer against small technical factors beyond control that could lead to significant differences in interpretation. Reporting of “resistance” indicates that anti-microbial concentrations in the urine are not usually achievable and that alternative therapies should be selected.
Standard drug sensitivity testing requires the use of laboratory-controlled microorganisms. Standard phosphomycin aminotriol powder in an agar dilution test containing 25 μg/mL glucose 6-phosphate should yield the following MIC values. [Broth dilution tests should not be performed].
MicrobesMIC (μg/mL)Enterococcus faecalis ATCC 2921232-128Eichia coli ATCC 259220.5-2Pseudomonas aeruginosa ATCC 278532-8Staphylococcus aureus ATCC 292130.5-4Diffusion method.
The quantitative method for measuring the diameter of the inhibition circle gives a repeatable estimate of bacterial susceptibility to antibiotics. This standard method requires the use of a standard inoculum concentration. This method uses inoculums of drug-sensitive paper inoculated with 200 μg of phosphomycin and 50 μg of glucose 6-phosphate to test the susceptibility of microorganisms to phosphomycin.
The standard single slice drug sensitivity test report obtained using drug-sensitive papers inoculated with 200 μg of phosphomycin and 50 μg of glucose 6-phosphate should be interpreted according to the following criteria.
Dia of inhibition circle (mm)Explanation≥ 16Sensitive(S)13-15Medium (I)≤ 12Resistant (R)The interpretation of results should be the same as above using the dilution method. The interpretation should involve the correlation of the diameter obtained from the drug-sensitive tablet test with the phosphomycin MIC.
As with the standard dilution method, the diffusion method requires the use of laboratory control microorganisms for the technical aspects of the control laboratory method. For the diffusion method, drug-sensitive paper tablets with 200 μg of phosphomycin and 50 μg of glucose 6-phosphate should yield the following inhibition circle diameters for these laboratory quality-controlled strains.
MicrobesInhibitory circle diameter (mm)E. coli ATCC 2592222-30 Staphylococcus aureus ATCC 25923 25-33Toxicological studies.
Carcinogenicity, mutagenicity and reproductive disorders
Long-term carcinogenicity studies were not performed using rodents, as phosphomycin aminotriol was intended for single administration for human treatment. Phosphomycin aminotriol was not mutagenic or genotoxic in the in vitro Ames bacterial reversion assay in cultured human granulocytes and Chinese hamster V79 cells and in the in vivo mouse micronucleus assay. Phosphomycin aminotriol did not affect reproduction or reproductive performance in male and female rats.
[Pharmacokinetics].
Absorption.
Fosfomycin aminotriol is rapidly absorbed and converted to free acid and phosphomycin after oral administration. The absolute oral bioavailability under fasting conditions was 37%. Maximum serum concentrations (Cmax) were reached within 2 hours after a single administration of 3 g of phosphomycin aminotriol pellets, with a mean (± 1 SD) of 26.1 (± 9.1) μg/mL. oral bioavailability of phosphomycin under fed conditions decreased to 30%. Cmax was reached within 4 hours after a single administration of 3 g of phosphomycin aminotriol pellets after a high-fat meal, with a mean value of 17.6 (± 4.4) μg/mL.
Cimetidine does not affect the pharmacokinetics of fosfomycin when given in combination with fosfomycin aminotriol pellets. Metoclopramide decreased serum concentrations and urinary excretion of fosfomycin when co-administered with fosfomycin aminotriol pellets (see [Precautions], [Drug Interactions]).
Distribution.
The mean apparent steady-state volume of distribution (Vss) following oral administration of phosphomycin aminotriol was 136.1 (±44.1) L. Phosphomycin is not bound to plasma proteins.
Fosfomycin is distributed to the kidney, bladder wall, prostate, and seminal vesicles. After administration of 50 mg/kg of phosphomycin to patients undergoing urologic surgery for bladder cancer, the mean concentration of phosphomycin collected 3 hours after administration at sites in the bladder away from the tumor was 18.0 μg/g tissue. Phosphomycin has been shown to cross the placental barrier in animals and humans.
Excretion.
Fosfomycin is excreted as a prototype in the urine and feces. After oral administration of phosphomycin aminotriol pellets, the mean systemic clearance (CLTB) and mean renal clearance (CLR) of phosphomycin were 16.9 (± 3.5) L/hr and 6.3 (± 1.7) L/hr, respectively. approximately 38% of 3 g of phosphomycin aminotriol pellets were recovered from the urine and 18% from the feces. After 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.
The mean concentration of phosphomycin obtained in urine 2-4 hours after a single administration of 3 g of phosphomycin aminotriol pellets under fasting conditions was 706 (± 466) μg/mL. The mean concentration of phosphomycin in urine in samples collected 72-84 hours after a single oral administration of phosphomycin aminotriol pellets was 10 μg/mL.
The mean concentration of phosphomycin in urine obtained within 6-8 hours of administration of 3 g of phosphomycin aminotriol pellets after a high-fat meal was 537 (± 252) μg/mL. Although the urinary excretion rate of phosphomycin was reduced under fed conditions, the urinary accumulation of phosphomycin was similar to that under fasting conditions, 1118 (± 201) mg (fed) and 1140 mg (± 238), respectively. (fasting). In addition, the time to maintain urine concentrations ≥100 μg/mL was the same for 26 hours in both conditions, indicating that phosphomycin aminotriol pellets can be taken with food.
The mean elimination half-life (t1/2) after oral administration of phosphomycin aminotriol pellets was 5.7 (± 2.8) hours.
Special Populations.
Elderly.
Based on limited data of 24-hour urinary drug concentrations, no difference in urinary excretion of fosfomycin was observed in elderly subjects. No dose adjustment was required in the elderly.
Gender.
There were no gender differences in the pharmacokinetics of fosfomycin.
Renal dysfunction.
In 5 anuric patients on hemodialysis, the t1/2 of fosfomycin during dialysis was 40 hours. In patients with varying degrees of renal dysfunction (creatinine clearance of 54 mL/min – 7 mL/min), phosphomycin t1/2 ranged from 11 to 50 hours. The percentage of phosphomycin recovered in urine decreased from 32% to 11%, suggesting that renal dysfunction significantly reduced phosphomycin excretion.
[Storage]Seal and store in a dry place.
[Package]Inside package is soda lime glass infusion bottle, halobutyl rubber stopper for injection (brominated) and aluminum-plastic combination cap for infusion bottle, 1 bottle/box.
[Effective period]18 months
[Executive Standard].
[Approval number]State Drug Administration H19994124
[Drug Marketing Authorization Holder
Name: Shanxi Qianyuan Pharmaceutical Group Co.
Registered office: No. 53, Hubin Street, Economic and Technological Development Zone, Datong, Shanxi Province
Company name: Shanxi Qian Yuan Pharmaceutical Group Co.
Production Address: No. 53, Hubin Street, Datong Economic and Technological Development Zone, Shanxi Province
Postcode: 037010
Phone number: 0352-6116505
Fax number: 0352-6116515
Website: www.cy-pharm.com