Fluorothiazinon (Tablets) Instructions for Use

Marketing Authorization Holder

FSBI N.F. Gamaleya NRCEM of the Ministry of Health of the Russian Federation (Medgamal Branch of the N.F. Gamaleya NRCEM of the Ministry of Health of the Russian Federation) (Russia)

ATC Code

V30 (Not assigned)

Active Substance

Ftortiazinon (Grouping name)

Dosage Form

Ftortiazinon

Tablets 300 mg: 14 pcs.

Dosage Form, Packaging, and Composition

Tablets round, biconvex, from almost white to yellow in color, yellow and black inclusions are allowed.

Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch, polyvinyl alcohol, sodium lauryl sulfate, magnesium stearate, macrogol 6000.

14 pcs. – polypropylene jars (1) – cardboard packs.

Pharmacological Action

The target of action of fluorothiazinone is the ATPase of the key pathogenicity factor of a wide range of gram-negative pathogenic bacteria – the type III secretion system (TTSS), as well as the flagellum, which play an important role in the pathogenicity of infectious disease agents.

Mechanism of action: specific suppression of mobility, toxin secretion, invasion, colonization, intracellular survival, and biofilm formation by pathogenic bacteria – Pseudomonas aeruginosa, Acinetobacter baumanii, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Chlamydia spp. For Enterococcus spp. and Staphylococcus aureus, suppression of biofilms has been demonstrated in vitro.

Acts on pathogenic extracellular and intracellular bacteria. Does not affect the qualitative and quantitative composition of the normal intestinal microflora.

Pharmacokinetics

After oral administration at a daily dose of 1800 mg (2 times/day with a 12-hour interval of 900 mg), Ftortiazinon is absorbed from the gastrointestinal tract at a rate (C_max/AUC_0-t) of 0.0496 ± 0.0180 h^-1. When taking a daily dose of 1800 mg, two concentration maxima of fluorothiazinone were observed – C_max (1) was 3.12±1.79 ng/ml after 3.20 ± 1.10 h, and C_max(2) – 2.43±1.42 ng/ml after 17.60 ± 2.19 h after the first dose. AUC_0-t and AUC_0-∞ were 68.59 ± 24.99 and 70.33 ± 28.95 ng/ml×h, respectively. T_1/2 was 26.56±11.85 h with k_el 0.031±0.014 h^-1 and a mean residence time MRT of 23.04±4.03 h.

Fluorothiazinone concentrations are characterized by significant interindividual variability; concentrations at a single time point vary from 45.1 to 86.6%.

During a course of administration at a daily dose of 1800 mg (900 mg with a 12-hour interval) for seven days, accumulation of free fluorothiazinone in the blood occurs; the concentration increased from 0.71±0.56 ng/ml to 2.89±1.95 ng/ml.

Steady state is reached on day 5 of the course of administration. The accumulation coefficient of unchanged fluorothiazinone R_acc is 2.67±1.77 (C₁₆₀/C₁₄). During the course of administration, a large interindividual variability in free fluorothiazinone concentrations is also noted throughout the entire course, with the coefficient of variation ranging from 46.11% (40 h) to 165% (4 h).

Calculation of the V_d value gave large results, indicating that Ftortiazinon is distributed in all body fluids and accumulates in tissues. The substance is predominantly in a tissue-distributed state, which is confirmed by preclinical study data. Ftortiazinon has pronounced lipophilicity (LogD 2.262) and high permeability through lipid membranes (up to 60%), indicating that the substance will be predominantly in a tissue-distributed state. Significant accumulation of fluorothiazinone in organs is confirmed by the results of preclinical studies; concentrations of free fluorothiazinone in organs exceed concentrations in the blood.

In the human body, Ftortiazinon is predominantly metabolized with the formation of conjugates with glucuronic acid (Phase II metabolism). In addition to the glucuronide, fluorothiazinone sulfate and Phase I metabolites – desethylfluorothiazinone and desfluorothiazinone – are detected in samples. The concentrations of sulfate, desethylfluorothiazinone, and desfluorothiazinone are insignificant and amount to a total intensity of 0.7% of the intensity of fluorothiazinone. The concentrations of the glucuronoconjugated metabolite are more than 20 times higher than the concentrations of free fluorothiazinone in whole blood and urine samples. The detection of a second peak of fluorothiazinone concentration suggests the presence of hepatic excretion and enterohepatic circulation. During enterohepatic recirculation, the compound itself or its glucuronoconjugate is involved in the process of bile acid recirculation, during which enzymatic hydrolysis of conjugates is also possible, leading to an increase in the concentration of the native compound in the intestine and blood.

Within 1.5 days, free Ftortiazinon is excreted in human urine in extremely small amounts. Within 36 hours after a daily dose of 1800 mg, an average of 0.56×10^-3% of the original compound was detected. Most of the calculated pharmacokinetic parameters show strong variation, ranging from 40.77 to 67.25%. Within 36 hours after a daily dose of 1800 mg, an average of 0.43% of the fluorothiazinone metabolite was detected.

Indications

In combination with cefepime for the treatment of complicated urinary tract infections caused by strains of the microorganisms Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae.

ICD codes

Dosage Regimen

Take the tablets orally.

The standard dosage for adults is 600 mg taken twice daily with an approximate 12-hour interval.

The total daily dose is 1200 mg.

The duration of treatment is typically 7 to 14 days.

Adjust the treatment duration based on the severity of the infection and the clinical response.

This medication is used exclusively in combination with cefepime for the specified indication.

Complete the full prescribed course of therapy even if symptoms improve.

Adverse Reactions

Infections and infestations uncommon – infection caused by fungi of the genus Candida.

Nervous system disorders common – headache.

Cardiac disorders uncommon – sinus bradycardia, sinus tachycardia.

Respiratory, thoracic and mediastinal disorders uncommon – rhinorrhea.

Gastrointestinal disorders common – diarrhea; uncommon – nausea, constipation, pain in the upper abdomen, abdominal pain, vomiting, dyspepsia.

Renal and urinary disorders uncommon – proteinuria.

Reproductive system and breast disorders uncommon – vulvovaginal itching.

Investigations common – increased blood urea level, increased CPK level, increased AST activity, decreased hemoglobin level; uncommon – increased ALT activity, increased ESR, increased blood bilirubin level, decreased platelet count, decreased relative granulocyte count, increased blood alkaline phosphatase level, increased blood creatinine level.

Contraindications

Hypersensitivity to fluorothiazinone.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

The safety of fluorothiazinone has not been studied in patients with hepatic insufficiency. It is impossible to give recommendations on the dosing regimen.

Use in Renal Impairment

The safety of fluorothiazinone has not been studied in patients with renal insufficiency. It is impossible to give recommendations on the dosing regimen.

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Pediatric Use

Safety and efficacy in children and adolescents under 18 years of age have not been studied.

Special Precautions

The safety of fluorothiazinone has not been studied in patients with renal and hepatic insufficiency, therefore, before starting treatment, it is necessary to assess liver and kidney function.

Drug Interactions

The potential for drug interactions of fluorothiazinone can be considered low.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.