Uronormin-F, 3 g 8 g

Pharmacotherapeutic group

Antibacterials other.

The ATX code: J01ХХ01

Pharmacological properties

Pharmacodynamics

Uronormin-F contains phosphomycin [mono (2-ammonium-2-hydroxymethyl-1,3-propanediol)(2R-cis)-(3-methyloxyranil) phosphonate], a broad spectrum antibacterial agent, a phosphonic acid derivative intended to treat urinary tract infections.

The mechanism of action is associated with inhibition of the first stage of synthesis of the bacterial cell wall. Being a structural analogue of phosphoenolpyruvate it competitively inhibits irreversibly the enzyme UDF-N-acetylglucosamienolpyruviltransferase which catalyzes the reaction of formation of UDF-N-acetyl-3-O-(1-carboxyvinyl)-D-glucosamine from phosphoenolpyruvate and UDF-N-acetyl-D-glucosamine. The drug is also able to reduce bacterial adhesion to the bladder mucosa, which can play the role of a predisposing factor for recurrent infections. The mechanism of action of the drug explains the absence of cross-resistance with other classes of antibiotics and mutual reinforcement of action with antibiotics of other classes, such as beta-lactam antibiotics.

Phosphomycin is active against a wide range of Gram-positive and Gram-negative microorganisms commonly isolated in urinary tract infections such as Escherichia coli, Citrobacter spp, Klebsiella spp, Proteus spp, Serratia spp, Pseudomonas aeruginosa, Enterrococcus faecalis.

The emergence of resistance in the laboratory is explained by mutations in the glpT and uhp genes, which control L-alpha-glycerophosphate and glucose phosphate transport, respectively.

Pharmacokinetics

Intake:

In oral administration phosphomycin is well absorbed from the intestine and achieves bioavailability of about 50%. Maximum concentration in plasma is observed 2-2.5 hours after oral administration and is 22-32 mg/l. The plasma elimination half-life is 4 hours. Intake with food slows absorption without affecting the concentration in the urine.

Distribution:

Phosphomycin is distributed in the kidneys, bladder wall, prostate and seminal glands. A steady urinary concentration of fosfomycin exceeding the Minimum Bacteriostatic Concentration (MBc) is reached 24-48 hours after oral administration. Fosfomycin does not bind to plasma proteins and crosses the placental barrier. After a single administration, fosfomycin is excreted into breast milk in small amounts.

Elimation:

Phosphomycin is excreted unchanged, mainly by the kidneys, through glomerular filtration (40-50 % of the dose taken is found in the urine), with a half-life of about 4 hours, and, to a lesser extent, with the feces (18-28 % of the dose). The occurrence of a second peak serum concentration 6 and 10 hours after drug administration suggests that the drug is subject to intestinal hepatic recirculation.

The pharmacokinetic properties of fosfomycin are independent of age and pregnancy. The drug cumulates in patients with renal insufficiency; a linear relationship between pharmacokinetic parameters of fosfomycin and glomerular filtration rate has been established.

Indications

Active ingredient

Composition

How to take, the dosage

Interaction

Metoclopramide. When concomitant use of fosfomycin and metoclopramide, which increases gastrointestinal motility, the concentration of fosfomycin in blood serum and its excretion in the urine are reduced. Other drugs that increase gastrointestinal motility may have a similar effect.

Probenecid. Probenecid should not be administered concomitantly with fosfomycin, because it has been proven to significantly reduce renal clearance and excretion of fosfomycin.

Probenecid when administered to healthy volunteers receiving fosfomycin infusion significantly decreased renal clearance, probably by inhibiting tubular secretion, resulting in lower urinary concentrations of the drug.

Therapeutic evaluation of the effects of metoclopramide and probenecid on urinary fosfomycin levels after their combined use with fosfomycin in women with acute urinary tract infection has not been performed. Based on data obtained in healthy volunteers, urinary concentrations of phosphomycin cannot exceed the bactericidal concentration for a long enough period of time to lead to a microbiological cure. None of these drugs should be administered concomitantly with fosfomycin.

Cimetidine. Cimetidine does not affect the pharmacokinetics or urinary concentrations of phosphomycin when used together.

Eating. Food intake delays the absorption of phosphomycin, which leads to a decrease in plasma Cmax and urinary concentrations. Therefore, it is recommended that fosfomycin tromethamine be taken on an empty stomach or at least 2-3 h after a meal.

Special Instructions

General

Only a single dose of fosfomycin should be used to treat acute cystitis. Repeated daily doses of fosfomycin did not improve clinical success rates or microbiological eradication compared with single-dose therapy, but did increase the incidence of adverse reactions.

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, including life-threatening reactions, have been reported during therapy with fosfomycin. If these reactions occur, adequate medical treatment is necessary, and reapplication of fosfomycin is not recommended.

Before prescribing fosfomycin to patients with severe renal impairment (creatinine Cl<30 ml/min) or to patients on hemodialysis, the ratio of benefit to potential risk should be assessed, since the primary route of excretion of fosfomycin is the kidneys.

Diseases associated with Clostridium difficile

Diseases associated with Clostridium difficile have been reported with many antibacterials, including fosfomycin. The severity of these diseases can range from mild diarrhea to life-threatening colitis. This diagnosis should be considered when observing patients with diarrhea or symptoms of colitis, pseudomembranous colitis, toxic megacolon or colonic perforation after use of any antibacterial agent. Clostridium difficile-associated disease has been reported to occur within 2 months of starting antibacterial agents.

Treatment with antibacterial drugs can alter the normal flora of the colon and in many cases lead to excessive growth of Clostridium difficile, which produces toxins A and B, contributing to disease leading to significant morbidity and mortality. Diseases associated with Clostridium difficile may be refractory to antimicrobial therapy.

When a diagnosis of Clostridium difficile-associated disease is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases usually respond to discontinuation of antibacterial drugs not directed against Clostridium difficile. In moderate to severe cases, administration of saline and electrolytes, protein supplements, and therapy with an antibacterial agent clinically effective against Clostridium difficile should be considered. Drugs that inhibit intestinal peristalsis should not be used in the treatment of Clostridium difficile-associated diseases because they may slow the excretion of Clostridium difficile and its toxins. Surgical evaluation should be performed on clinical indications, since some severe cases may require surgical intervention.

Sensitivity/Resistance

The use of phosphomycin in the absence of proven or suspected bacterial infection may not be effective and may lead to the development of drug-resistant bacteria.

Pediatric use

The safety and effectiveness of fosfomycin in children under 18 years of age has not been established.

Impact on the ability to drive vehicles and operate machinery. Although there have been no studies of the effect on the ability to drive and operate machinery, dizziness has been reported in patients who have taken fosfomycin. This may affect the ability of some patients to drive vehicles and operate machinery.

Contraindications

Side effects

In three U.S. studies, 1,233 patients received therapy with fosfomycin. The most frequent adverse reactions that occurred in >1% of patients, regardless of association with drug use, 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%), asthenia (1.7%) and rash (1.4%).

In addition, the following adverse reactions were observed with a frequency of less than 1%: Stool disorders, anorexia, constipation, dry mouth, dysuria, hearing loss, fever, flatulence, flu-like syndrome, hematuria, infections, insomnia, lymphadenopathy, menstrual disorders, migraine, myalgia, nervousness, paresthesia, itching, skin conditions (skin disorders) and vomiting.

In the U.S. study population, statistically significant laboratory changes reported without drug association included increased eosinophil counts, increased or decreased white blood cell counts, increased bilirubin, ALT and AST levels, ALP, decreased hematocrit, Hb levels, and increased and decreased platelet counts. The changes were usually transient, clinically insignificant, and occurred in less than 1% of patients.

In the same population, there have been studies of adverse adverse reactions that were considered associated with fosfomycin administration and occurred in more than 1% of patients receiving fosfomycin. They included diarrhea (9%), vaginitis (5.5%), nausea (4.1%), headache (3.9%), dizziness (1.3%), asthenia (1.1%), and dyspepsia (1.1%). The most frequently observed reaction, diarrhea, was considered mild and transient (passed without any intervention).

One case of unilateral optic neuritis has been reported and was considered probably associated with fosfomycin use.

In the post-registration period of fosfomycin use, there have been reports of vulvovaginitis, tachycardia, hearing impairment, urticaria and anaphylactic reactions, including anaphylactic shock and hypersensitivity. Cases of angioedema, aplastic anemia, asthma (exacerbation), cholestatic jaundice, general reduction in taste sensation, hepatic necrosis, metallic taste in the mouth, and vestibular disorders have also been reported. One case of toxic megacolon has been reported and was found to be unrelated to phosphomycin administration.

Overdose

The data on fosfomycin overdose with oral administration are limited.

Symptoms: in cases of overdose during parenteral use hypotension, somnolence, disorders of water-electrolyte balance, thrombocytopenia and hypoprothrombinemia have been reported.

Treatment: in case of overdose symptomatic and supportive therapy should be carried out. Excretion of fosfomycin with urine should be stimulated by adequate fluid intake.

Pregnancy use

Fosfomycin crosses the placental barrier and its safety in the treatment of infections during pregnancy has not been established. Fosfomycin should be used during pregnancy only for absolute indications and only after considering the ratio of potential benefit to the mother and risk to the fetus.

Fosfomycin may be excreted into the breast milk, a decision should be made to stop breastfeeding or to discontinue use of fosfomycin after considering the potential benefit to the mother and risk to the newborn.

Similarities