Tigacil 50 mg N10 lyophilisate for solution preparation

Release form

lyophilisate for the preparation of solution for infusion

Package

10 pieces.

pharmachologic effect

Tigacil is an antibiotic of the glycylcycline group, structurally similar to tetracyclines. Inhibits protein translation in bacteria by binding to the 30S subunit of ribosomes and blocking the penetration of aminoacyl-tRNA molecules into the A-site of the ribosome, which prevents the inclusion of amino acid residues in growing peptide chains. Tigecycline is believed to have bacteriostatic properties. At 4 times the MIC of tigecycline, a two orders of magnitude decrease in the number of colonies of Enterococcus spp., Staphylococcus aureus and Escherichia coli was observed. The bactericidal effect of tigecycline was noted against Streptococcus pneumoniae, Haemophilus influenzae and Legionella pneumophila.

Indications

- complicated infections of the skin and soft tissues;

- complicated intra-abdominal infections;

- community-acquired pneumonia.

Contraindications

- hypersensitivity to the components of the drug;

- increased sensitivity to tetracycline antibiotics.

Carefully

The drug should be used for severe liver failure.

Use during pregnancy and breastfeeding

During pregnancy, the use of Tigacil is permissible only in cases of extreme necessity, when the benefit to the mother outweighs the possible risk to the fetus. There are no data on the excretion of tigecycline into breast milk in humans. If it is necessary to prescribe tigecycline during lactation, breastfeeding should be stopped. There is no experience with the use of the drug Tigacil during childbirth.

special instructions

To reduce the development of resistance and ensure the effectiveness of therapy, it is necessary to use Tigacil only for the treatment and prevention of infectious diseases caused by sensitive microorganisms. To select and adjust antibacterial therapy, if possible, microbiological identification of the pathogen should be carried out and its sensitivity to tigecycline should be determined. Tigacil can be used for empirical antibacterial monotherapy until the results of microbiological tests are obtained. Antibiotics belonging to the glycylcycline class are structurally similar to antibiotics from the tetracycline class. Tigacil can cause adverse reactions similar to adverse reactions to antibiotics of the tetracycline class. Such reactions may include increased photosensitivity, intracranial hypertension, pancreatitis and anti-anabolic effects leading to increased blood urea nitrogen, azotemia, acidosis and hypophosphatemia. Therefore, Tigacil should be used with caution in patients with known sensitivity to tetracycline antibiotics. Anaphylactic/anaphylactoid reactions, incl. anaphylactic shock is observed with the use of almost all antibacterial agents, including Tigacil. Patients who experience changes in liver test results during treatment with Tigacil should be observed to promptly identify signs of liver dysfunction (single cases of significant liver dysfunction and liver failure have been reported) and to assess the benefit-risk ratio of continuing Tigacil therapy. The development of undesirable reactions is possible after therapy has been completed. The effectiveness and safety of Tigacil in patients with hospital-acquired pneumonia has not been confirmed by the results of clinical studies. Diarrhea associated with Clostridium difficile has been reported when taking almost all antibacterial drugs, including Tigacil. If Clostridium difficile-associated diarrhea is suspected or confirmed, it may be necessary to discontinue use of antibiotics other than those prescribed to treat Clostridium difficile infection. When using tigecycline, the development of pseudomembranous colitis of varying severity is possible. The possibility of such a diagnosis should be considered if diarrhea occurs during or after completion of treatment. When prescribing Tigacil to patients with complicated intra-abdominal infections due to intestinal perforation, or patients with incipient sepsis or septic shock, the advisability of using combination antibacterial therapy should be considered. The use of Tigacil, like any other antibiotic, can promote excessive growth of non-susceptible microorganisms, including fungi. Patients should be closely monitored during treatment. When superinfection is diagnosed, appropriate measures should be taken. The effect of cholestasis on the pharmacokinetics of tigecycline has not been established. Excretion in bile accounts for approximately 50% of the total excretion of tigecycline. Therefore, patients with cholestasis should be under medical supervision. Experience with the use of Tigacil for the treatment of infections in patients with severe concomitant diseases is limited. The use of Tigacil during the formation of teeth can lead to a change in the color of the teeth to yellow, gray, or brown. Tigacil should not be used during tooth development unless other drugs are ineffective or contraindicated.

Compound

1 bottle contains tigecycline 50 mg.

Directions for use and doses

The drug Tigacil is administered intravenously over 30-60 minutes. The initial dose for adults is 100 mg, then 50 mg every 12 hours. The course of treatment for complicated infections of the skin and soft tissues, as well as complicated intra-abdominal infections is 5-14 days, for community-acquired pneumonia - 7-14 days. The duration of treatment is determined by the severity and location of the infection and the patient's clinical response to treatment. Patients with mild to moderate liver dysfunction (classes A and B on the Child-Pugh scale) do not require dose adjustment. For patients with severe liver failure (class C on the Child-Pugh scale), after administration of an initial dose of Tigacil 100 mg, the drug is subsequently prescribed 25 mg every 12 hours; In this case, it is necessary to be careful and monitor the patient's response to treatment. Patients with renal failure and patients on hemodialysis do not require dose adjustment of the drug. Elderly patients do not require dose adjustment of the drug.

Side effects

Most common: nausea (26%) and vomiting (18%), which usually occur at the beginning of treatment (on day 1 or 2 of treatment) and, in most cases, have a mild or moderate course. The most common reasons for discontinuation of Tigacil therapy were nausea (1%) and vomiting.

Classification of side effects: very often (≥ 1/10); often (from ≥ 1/100 to

From the blood coagulation system:

often - increase in aPTT, prothrombin time/MHO.

From the hematopoietic system:

sometimes - eosinophilia; in isolated cases - thrombocytopenia.

Allergic reactions:

in isolated cases - anaphylactic/anaphylactoid reactions.

From the side of the central nervous system:

often - dizziness.

From the cardiovascular system:

often - phlebitis; sometimes - thrombophlebitis.

From the digestive system:

very often - nausea, vomiting, diarrhea; often - abdominal pain, dyspepsia, anorexia; sometimes - acute pancreatitis; increased activity of AST and ALT - in serum, hyperbilirubinemia; sometimes - jaundice; in isolated cases - severe liver dysfunction and liver failure.

Dermatological reactions:

often - itching, rash.

From the reproductive system:

sometimes - vaginal candidiasis, vaginitis, leukorrhea.

Local reactions:

sometimes - inflammation, pain, swelling and phlebitis at the injection site

Other:

often - headache, asthenia, delayed wound healing; sometimes - chills.

From the laboratory parameters:

often - increased blood urea nitrogen, increased serum alkaline phosphatase activity, increased serum amylase activity, hypoproteinemia; sometimes - increased creatinine in the blood, hypocalcemia, hyponatremia, hypoglycemia.

Drug interactions

With the concomitant use of Tigacil and warfarin (in a single dose of 25 mg), there is a decrease in the clearance of R-warfarin and S-warfarin by 40% and 23%, a decrease in the AUC of warfarin by 68% and 29%, respectively. The mechanism of such interaction has not yet been established. Since tigecycline can increase both prothrombin time/INR and aPTT, when using Tigacil simultaneously with anticoagulants, it is necessary to carefully monitor the results of appropriate coagulation tests. Warfarin does not change the pharmacokinetic profile of Tigacil.

Tigecycline is not metabolized by isoenzymes of the cytochrome P450 system. Therefore, it is expected that active substances that suppress or induce the activity of isoenzymes of the cytochrome P450 system will not change the clearance of Tigacil. In turn, Tigacil is unlikely to affect the metabolism of these groups of medicinal compounds.

Tigacil at the recommended dose does not affect the rate and extent of absorption or clearance of digoxin (500 mcg followed by a daily dose of 250 mcg). Digoxin does not change the pharmacokinetic profile of tigecycline. Therefore, when using Tigacil together with digoxin, no dose adjustment is required.

When antibiotics are used concomitantly with oral contraceptives, the effectiveness of the contraceptives may be reduced.

In in vitro studies, antagonism was not observed between tigecycline and other commonly used classes of antibiotics.

Compatibility

Tigacil is compatible with 0.9% sodium chloride solution, 5% dextrose injection or lactated Ringer's solution. При назначении через Т-образный катетер Тигацил растворенный в 0.9% растворе натрия хлорида или 5% растворе декстрозы для инъекций совместим с амикацином, добутамином, допамина гидрохлоридом, гентамицином, галоперидолом, раствором Рингера лактата, лидокаина гидрохлоридом, метоклопрамидом, морфином, норэпинефрином, пиперациллином/ tazobactam (a dosage form containing EDTA), potassium chloride, propofol, ranitidine hydrochloride, theophylline and tobramycin.

Incompatibility

When used through a T-shaped catheter, Tigacil is incompatible with amphotericin B, liposomal amphotericin B, diazepam, esomeprazole and omeprazole.

Overdose

An overdose of Tygacil has not been described.

IV administration of tigecycline to healthy volunteers at a dose of 300 mg over a 60-minute administration period resulted in an increase in nausea and vomiting.

Hemodialysis does not remove tigecycline from the body.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C.

Conditions for dispensing from pharmacies

On prescription

Tigecycline PSK

An antibiotic of the glycylcycline group, structurally similar to tetracyclines. Inhibits protein translation in bacteria by binding to the 30S subunit of ribosomes and blocking the penetration of aminoacyl-tRNA molecules into the A-site of the ribosome, which prevents the inclusion of amino acid residues in growing peptide chains.

Tigecycline is believed to have bacteriostatic properties. At 4 times the MIC of tigecycline, a two orders of magnitude decrease in the number of colonies of Enterococcus spp., Staphylococcus aureus and Escherichia coli was observed.

The bactericidal effect of tigecycline was noted against Streptococcus pneumoniae, Haemophilus influenzae and Legionella pneumophila.

Gram-positive aerobic microorganisms are sensitive to tigecycline: Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis (including vancomycin-sensitive strains), Enterococcus faecalis (including vancomycin-resistant strains), Enterococcus gallinarum, Staphylococcus aureus (including methicillin-sensitive and resistant strains), Staphylococcus epidermidis (including methicillin-sensitive and resistant strains), Staphylococcus haemolyticus, Streptococcus agalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius and S. constellatus), Streptococcus pyogenes, Streptococcus pneumoniae (penicillin-susceptible strains), Streptococcus pneumoniae (penicillin -resistant strains), Streptococcus viridans group; gram-negative aerobic microorganisms: Aeromonas hydrophilia, Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli (including strains producing broad-spectrum beta-lactamase), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae (including strains producing β -broad spectrum lactamase), Legionella pneumophila, Moraxella catarrhalis, Serratia marcescens, Bacteroides fragilis group, Clostridium perfringens, Peptostreptococcus spp., Peptostreptococcus micros, Prevotella spp.; atypical microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae.

For Acinetobacter spp., Streptococcus pneumoniae, other streptococci, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoea and Neisseria meningitidis, there is no convincing evidence of the effectiveness of tigecycline.

The effectiveness of tigecycline for the treatment of intra-abdominal infections caused by anaerobic bacteria has been established, regardless of MIC and pharmacokinetic/pharmacodynamic parameters. Therefore, reference MIC values are not presented. It should be noted that tigecycline has a wide range of MICs for Bacteroides spp. and Clostridium spp., in some cases exceeding 2 mg/l.

There are only limited data on the clinical effectiveness of tigecycline for enterococcal infections. However, a positive response to tigecycline treatment for polymicrobial intra-abdominal infections has been shown.

The prevalence of acquired resistance in individual bacterial species may vary over time and geographical location.

Species that may develop acquired resistance: Acinetobacter baumannii, Burkholderia cepacia, Morganella morganii, Providencia spp., Proteus spp., Stenotrophomonas maltophilia.

Microorganisms with their own resistance: Pseudomonas aeruginosa.

Tigecycline can overcome the two main mechanisms of microbial resistance observed with tetracyclines: ribosomal protection and active clearance. In addition, the activity of tigecycline is not inhibited by the action of β-lactamases (including extended-spectrum β-lactamases), or by modification of antibiotic-sensitive sites of the bacterial membrane, or by active removal of the antibiotic from the bacterial cell or by modification of the target of action (for example, gyrase/topoisomerase). Thus, tigecycline has a broad spectrum of antibacterial activity. However, tigecycline lacks protection against the resistance mechanism of microorganisms in the form of active clearance from the cell, encoded by the chromosomes of Proteeae and Pseudomonas aeruginosa (MexXY-OprM efflux system). There is no cross-resistance between tigecycline and most classes of antibiotics.

In general, microorganisms belonging to Proteus spp., Providencia spp. and Morganella spp., are less sensitive to tigecycline than other members of Enterobacteriaceae. In addition, some acquired resistance has been found in Klebsiella pneumoniae, Enterobacter aerogenes and Enterobacter cloacae. The reduced sensitivity of representatives of both groups to tigecycline is due to overexpression of the gene for nonspecific active elimination of Ac-AB, which provides resistance to many drugs. Reduced sensitivity to tigecycline and Acinetobacter baumannii has been described.

Pharmacokinetics.

Since tigecycline is administered intravenously, it is characterized by 100% bioavailability.

At concentrations from 0.1 to 1 μg/ml, the binding of tigecycline to plasma proteins in vitro varies from approximately 71% to 89%. Pharmacokinetic studies in animals and humans have shown that tigecycline is rapidly distributed into tissues.

In the human body, the equilibrium Vd of tigecycline is 500-700 l (7-9 l/kg), which confirms the extensive distribution of tigecycline outside the plasma and its accumulation in tissues.

There are no data on the ability of tigecycline to penetrate the BBB in the human body.

Cssmax of tigecycline in serum was 866+233 ng/ml with 30-minute infusions and 634+97 ng/ml with 60-minute infusions. AUC0-12 hours was 2349+850 ng×hour/ml.

On average, less than 20% of tigecycline is metabolized. The main substance found in urine and feces was unchanged tigecycline, but a glucuronide, an N-acetyl metabolite, and an epimer of tigecycline were also detected.

Tigecycline does not suppress metabolism mediated by the following six isoenzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. It is neither a competitive inhibitor nor an irreversible inhibitor of cytochrome P450.

It was noted that 59% of the prescribed dose is excreted through the intestines (with most of the unchanged tigecycline entering the bile), and 33% is excreted by the kidneys. Additional routes of elimination are glucuronidation and excretion of unchanged tigecycline by the kidneys.

The total clearance of tigecycline after intravenous infusion is 24 l/h. Renal clearance accounts for approximately 13% of total clearance. Tigecycline is characterized by polyexponential elimination from serum, the average terminal T1/2 from serum after administration of repeated doses is 42 hours, but significant individual differences are observed.

In patients with moderate to severe hepatic impairment (Child-Pugh class B and C), the total clearance of tigecycline was reduced by 25% and 55%, and T1/2 was increased by 23% and 43%, respectively.

In patients with severe renal impairment, AUC is 30% greater than in patients with normal renal function.

Clearance, incl. normalized by body weight, and AUC did not differ significantly in patients with different body weights, including those exceeding 125 kg. In patients weighing more than 125 kg, the AUC value was 25% lower. There are no data on patients weighing more than 140 kg.

Tigacil®

To select and adjust antibacterial therapy, if possible, microbiological identification of the pathogen should be carried out and its sensitivity to tigecycline should be determined. Tigacil can be used for empirical antibacterial monotherapy until the results of microbiological tests are obtained.

Antibiotics belonging to the glycylcycline class are structurally similar to antibiotics from the tetracycline class. Tigacil may cause adverse reactions similar to those seen with tetracycline class antibiotics. Such reactions may include increased photosensitivity, intracranial hypertension, pancreatitis and anti-anabolic effects leading to increased blood urea nitrogen, azotemia, acidosis and hypophosphatemia. Therefore, Tigacil should be used with caution in patients with known sensitivity to tetracycline antibiotics.

Anaphylactic/anaphylactoid reactions, including anaphylactic shock, are observed with the use of almost all antibacterial agents, including Tigacil.

Patients who experience changes in liver test results during treatment with Tigacil should be observed for timely detection of signs of liver dysfunction (single cases of significant liver dysfunction and liver failure have been reported) and to assess the balance of benefits. and the risk of continuing therapy with Tigacil.

Adverse reactions may develop after therapy has been completed.

The effectiveness and safety of Tigacil in patients with hospital-acquired pneumonia has not been confirmed by the results of clinical studies.

Diarrhea of varying severity associated with Clostridium difficile has been observed when taking almost all antibacterial drugs, including Tigacil. The possibility of such a diagnosis should be considered if diarrhea occurs during or after completion of treatment. If Clostridium difficile-associated diarrhea is suspected or confirmed, it may be necessary to discontinue use of antibiotics other than those prescribed to treat Clostridium difficile infection.

When prescribing Tigacil to patients with complicated intra-abdominal infections due to intestinal perforation, or patients with incipient sepsis or septic shock, the advisability of using combination antibacterial therapy should be considered.

The use of Tigacil, like any other antibiotic, can promote excessive growth of non-susceptible microorganisms, including fungi. During treatment, patients should be closely monitored. When superinfection is diagnosed, appropriate measures should be taken.

The effect of cholestasis on the pharmacokinetics of tigecycline has not been established. Excretion in bile accounts for approximately 50% of the total excretion of tigecycline. Therefore, patients with cholestasis should be under medical supervision.

Experience with the use of Tigacil for the treatment of infections in patients with severe concomitant diseases is limited.

The use of Tigacil during the formation of teeth can lead to a change in the color of the teeth to yellow, gray, or brown. Tigacil should not be used during tooth development unless other drugs are ineffective or contraindicated.

There are reports of the development of acute pancreatitis while taking Tigacil, in some cases with a fatal outcome. Caution should be exercised when using Tigacil in patients with suspected acute pancreatitis (clinical symptoms or corresponding changes in laboratory parameters). There are known cases of the development of acute pancreatitis in patients who did not have risk factors for the development of this disease. Typically, symptoms of pancreatitis disappear after discontinuation of the drug. It is necessary to consider the possibility of drug withdrawal in patients with symptoms of pancreatitis.

In clinical studies, an increase in overall mortality was noted compared with comparators. The reasons for the increase in mortality are not clear. It is recommended to take this into account when choosing antibiotic therapy.