Tigacil lyophilizate 50mg vials, 10pcs

Composition

1 bottle of lyophilizate for the preparation of an infusion solution contains:

• Active ingredient:
• tigecycline 50 mg,

excipients:

• lactose monohydrate,
• hydrochloric acid q. s to pH,
• sodium hydroxide q. s to pH.

Pharmacological action

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 to 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. With a 4-fold MPC of tigecycline, the number of Enterococcus spp., Staphylococcus aureus, and Escherichia coli colonies decreased by two orders of magnitude.

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

Sustainability development mechanism

Tigecycline can overcome two main mechanisms of microbial resistance observed against tetracyclines: ribosomal protection and active elimination.

In addition, tigecycline activity is not suppressed by the action of beta-lactamases (including extended-spectrum beta-lactamases), nor by modification of antibiotic-sensitive areas of the bacterial envelope, nor by active removal of the antibiotic from the bacterial cell or modification of the target of exposure (for example, gyrase/topoisomerase).

Thus, tigecycline has a broad spectrum of antibacterial activity. However, tigecycline lacks protection against the mechanism of microbial resistance in the form of active elimination from the cell, encoded by the Proteeae and Pseudomonas aeruginosa chromosomes(MexXY-OprM outflow 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 the Enterobacteriaceae. In addition, some acquired resistance was found in Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae.

Reduced sensitivity of representatives of both groups to tigecycline is due to overexpression of the gene for non-specific active elimination of AsgAV, which provides resistance to many drugs. Reduced sensitivity to tigecycline and Acinetobacter baumannii is described.

MPC reference values

The BMD reference values set by the European Working Group on Antibiotic Sensitivity Testing (EUCAST) are listed below.

* Reduced activity of tigecycline in vitro against Proteus spp., Providencia spp. and Morganella spp. was noted.

For Acinetobacter spp., Streptococcus pneumoniae, other streptococci, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoea, and Neisseria meningitidis, no conclusive evidence has been obtained for the efficacy of tigecycline.

The efficacy of tigecycline for the treatment of intraabdominal infections caused by anaerobic bacteria was established, regardless of BMD parameters, pharmacokinetic / pharmacodynamic parameters. Therefore, the MPC reference values are not presented.

A wide range of MPC of tigecycline for Bacteroides spp. and Clostridium spp. should be noted, in some cases exceeding 2 mg/l.

There are only limited data on the clinical efficacy of tigecycline in enterococcal infections. Nevertheless, a positive response to treatment with tigecycline for polymicrobial intraabdominal infections has been shown.

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

Gram-positive aerobic microorganisms are sensitive to the drug:

Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis1,2 (including vancomycin-sensitive strains), Enterococcus faecalis (including vancomycin-resistant strains), Enterococcus gallinarum, Staphylococcus aureus1,2 (including methicillin-sensitive and resistant strains), Staphylococcus epidermidis (including methicillin-sensitive and resistant strains), Staphylococcus haemolyticus, Streptococcus agalactiae1, group Streptococcus anginosus1,2 (including S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes1, Streptococcus pneumoniae3 (penicillin-susceptible strains), Streptococcus pneumoniae (penicillin-resistant strains)the viridans group Streptococci;

aerobic gram-negative microorganisms: Aeromonas hydrophilia, freundii2 Citrobacter, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae2, Escherichia coli1,2 (including strains producing beta-lactamases broad-spectrum), influenzae3 Haemophilus, Haemophilus parainfluenzae, Klebsiella oxytoca2, Klebsiella pneumoniae1,2 (including strains producing β-lactamases broad-spectrum), pneumophila3 Legionella, Moraxella catarrhalis, Serratia marcescens, Bacteroides fragilis group1,2, perfringens2 Clostridium, Peptostreptococcus spp. 2, Peptostreptococcus micros, Prevotella spp. ; atypical microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae.

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

Microorganisms that have their own resistance: Pseudomonas aeruginosa.

1,2,3 – species for which satisfactory activity has been demonstrated in clinical studies.

Pharmacokinetics

Suction

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

Distribution

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

In humans, 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 cross the BBB in humans.

C_ssmax of tigecycline in serum was 866±233 ng / ml at 30-minute infusions and 634±97 ng / ml at 60-minute infusions. The AUC_{of 0-12 h} was 2349±850 ng×h / ml.

Metabolism

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

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

Deduction

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

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 T_1/2 from serum after repeated doses is 42 hours, but significant individual differences are observed.

Pharmacokinetics in special clinical cases

In patients with mild hepatic impairment, the pharmacokinetic profile of a single dose of tigecycline does not change.

However, in patients with moderate and severe hepatic impairment (Child-Pugh class B and C), total clearance of tigecycline was reduced by 25% and 55%, and T_1/2 increased by 23% and 43%, respectively.

In patients with renal insufficiency (CC

), the pharmacokinetics of tigecycline in elderly patients generally did not differ from other age groups.

The pharmacokinetics of tigecycline in patients younger than 18 years of age have not been studied.

Clinically significant differences in the clearance of tigecycline in men and women have not been established.

The clearance of tigecycline does not depend on race.

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

Indications

• Complicated skin and soft tissue infections;
• complicated intra-abdominal infections;
• community-acquired pneumonia.

Use during pregnancy and lactation

During pregnancy, the use of Tigacil is permissible only in cases of extreme necessity, when the benefit to the mother exceeds the possible risk to the fetus.

There are no data on the elimination of tigecycline in human breast milk.

If it is necessary to prescribe tigecycline during lactation, stop breastfeeding. Experience of using the drug Tigacil is not available during labor.

Contraindications

Hypersensitivity to the components of the drug Tigacil;  hypersensitivity to tetracycline antibiotics.

The drug should be used with caution in patients with severe hepatic insufficiency.

Side effects

The most common symptoms are nausea (29.9%) and vomiting (19.9%), which usually occur at the beginning of treatment (on the first or second day of treatment) and, in most cases, have a mild or moderate course. The most common reasons for discontinuation of Tigacil therapy were nausea (1.6%) and vomiting (1.3%).

Side effects are classified by organ and system: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to

From the side of the blood system and hematopoietic organs:

• Often: increased activated partial thromboplastin time (APTT), increased prothrombin time (PV), anemia, thrombocytopenia.

• Infrequently: eosinophilia, increased international normalized ratio (INR).

From the immune system:

• Isolated cases: anaphylactic / anaphylactoid reactions.

Nervous system disorders:

• Often: dizziness, headache.
• Infrequently: perversion of taste.

From the cardiovascular system:

• Common: phlebitis.
• Infrequently: thrombophlebitis.

From the gastrointestinal tract:

• Very common: nausea, vomiting, diarrhea.
• Common: abdominal pain, dyspepsia, anorexia.
• Infrequently: acute pancreatitis.

From the side of the hepatobiliary system:

• Often: increased activity of aspartate aminotransferase (AST) – in blood plasma*, increased activity of alanine aminotransferase (ALT) in blood plasma*, hyperbilirubinemia.
• Infrequently: jaundice.
• Isolated cases: severe liver dysfunction and liver failure, cholestasis.

From the skin and subcutaneous fat

• Often: itching, rash.
• Isolated cases: severe skin reactions, including Stevens-Johnson syndrome.

From the genitourinary system:

• Infrequently: vaginal candidiasis, vaginitis, leukorrhea.

General reactions and injection site reactions:

• Common: asthenia, delayed wound healing, abscess, infection, injection site reactions, sepsis.
• Infrequently: inflammation, pain, swelling and phlebitis at the injection site, chills, septic shock, allergic reactions.

Laboratory parameters:

• Often: increased blood urea nitrogen, increased activity of alkaline phosphatase in blood plasma, increased activity of amylase in blood plasma hypoproteinemia.
• Infrequently: increased blood creatinine, hypocalcemia, hyponatremia, hypoglycemia.

Respiratory system disorders:

• Common: pneumonia.

Antibiotic-specific reactions: pseudomembranous colitis.

* increased ALT and AST activity was observed more frequently after the end of Tigacil®therapy.

A combined analysis of clinical data from 13 phase 3 and 4 trials on the use of Tigacil® for registered and unregistered indications revealed a high overall mortality rate (i. e., death from any cause, including non-treatment-related ones) in patients with severe infections treated with Tigacil®.

Overall mortality in patients treated with Tigacil® was 4% (150/3788), comparison drugs-3% (110/3646), the difference in the relative risk of death – 0.6% (confidence interval (CI): 0.1 – 1.2).

The causes of increased overall mortality in patients treated with Tigacil® have not been established. In general, deaths were the result of worsening of the infection, complications of infection, or concomitant diseases.

Data on the use of tigecycline in children are limited to two pharmacokinetic studies and one open-label clinical study in a small group of children. No new or unexpected data on the safety of the drug were found in these studies.

In an open-label pharmacokinetic study with a single dose escalation, the safety of tigecycline was evaluated in 25 paediatric patients (aged 8 to 16 years) who had recently had an infectious disease.

The profile of side effects in children was generally similar to that in adults.

The safety of tigecycline was also studied in 58 paediatric patients (8-11 years old), with complicated skin and soft tissue infections (15 patients), complicated intra-abdominal infections (24 patients), or community-acquired pneumonia (19 patients).

The adverse event profile of these 58 patients was similar to that of adults, with the exception of nausea (48.3%), vomiting (46.6%), and elevated plasma lipase levels (6.9%), which were more common in children than in adults.

Interaction

Compatibility/incompatibility with medicinal products and solvents when administered concomitantly

Compatibility

Tigacil® is compatible with 0.9% sodium chloride solution,5% dextrose solution for injection or Ringer’s lactate solution.

When administered via a T-shaped catheter, Tigacil® dissolved in 0.9% sodium chloride solution or 5% dextrose solution for injection is compatible with amikacin, dobutamine, dopamine, gentamicin, haloperidol, Ringer’s lactate solution, lidocaine, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (dosage form containing ethylenediaminetetraacetate – EDTA), potassium chloride, propofol, ranitidine, theophylline and tobramycin.

Incompatibility

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

Warfarin

Concomitant use of Tigacil® and warfarin (a single dose of 25 mg) resulted in a 40% and 23% decrease in the clearance of R-warfarin and S-warfarin, and a 68% and 29% increase in the AUC of warfarin, respectively.

The mechanism of such interaction has not yet been established. Since tigecycline can prolong both PV / INR and APTT, when using Tigacil ® simultaneously with anticoagulants, it is necessary to carefully monitor the results of appropriate coagulation tests.

Warfarin does not alter the pharmacokinetic profile of tigecycline.

Inhibitors or inducers of cytochrome P 450 isoenzymes

Tigecycline is not metabolized by cytochrome P450 isoenzymes. Therefore, it is expected that active substances that inhibit or induce the activity of cytochrome P450 isoenzymes will not alter the clearance of tigecycline.

In turn, Tigacil® is unlikely to affect the metabolism of these groups of drug compounds.

In vitro studies have shown that tigecycline does not inhibit the metabolism mediated by the following six cytochrome CYP isoenzymes: 1A2,2C8,2C9,2C19,2D6, and 3A4.

Digoxin

Tigacil® at the recommended dose does not affect the rate and degree of absorption or clearance of digoxin (0.5 mg followed by a daily dose of 0.25 mg).

Digoxin does not alter the pharmacokinetic profile of tigecycline. Therefore, when using Tigacil® together with digoxin, no dose adjustment is required.

Concomitant use of P-glycoprotein inhibitors (e. g. ketoconazole or cyclosporine) or P-glycoprotein inducers (e. g. rifampicin) may affect the pharmacokinetics of tigecycline.

Oral contraceptives

When using antibiotics simultaneously with oral contraceptives, the effectiveness of contraceptives may decrease.

Antagonism between tigecycline and other commonly used antibiotics was not observed in in vitro studies.

How to take, course of use and dosage

Intravenously, drip for 30-60 minutes (see “Instructions for preparation of the solution and use of the drug”).

The initial dose for adults is 100 mg, then 50 mg every 12 hours.

Course of treatment:

– for complicated skin and soft tissue infections, as well as complicated intraabdominal infections,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.

Liver failure

Patients with mild to moderate hepatic insufficiency (Child-Pugh class A and B) do not require dose adjustment.

In patients with severe hepatic insufficiency (Child-Pugh class C), the dose of the drug should be reduced by 50%. The initial dose of Tigacil® should be 100 mg, and then the drug is used for 25 mg every 12 hours.

When using Tigacil® in patients with severe hepatic insufficiency, caution should be exercised and the patient’s response to treatment should be monitored.

Renal insufficiencypatients with renal insufficiency and patients on hemodialysis do not require dose adjustment.

Elderly patients: No dose adjustment is required.

Use in children Efficacy and safety in children under 8 years of age has not been established.

Tigecycline is used in children aged 8 years and older after consultation with a specialist with experience in the treatment of infectious diseases. Tigecycline should not be used in children under 8 years of age due to the lack of data on the effectiveness and safety of the drug in this group, as well as in view of changes in tooth color (see the section “Special instructions”).

The dose for children aged 8-11 years is 1.2 mg / kg every 12 hours. The maximum dose is 50 mg of tigecycline every 12 hours.

The dose for children aged 12-17 years is 50 mg of tigecycline every 12 hours.

Intravenous infusion of tigecycline should be continued for 30-60 minutes every 12 hours.

Instructions for preparation of the solution and use of the drug

Preparation

Before use, dilute the contents of each vial of Tigacil® with 0.9% sodium chloride solution,5% dextrose solution for injection or Ringer’s lactate solution in an amount of 5.3 ml to obtain a ready-made solution with a tigecycline concentration of 10 mg / ml.

(Note: 5 ml of the finished solution contains 50 mg of tigecycline, each vial contains an excess of 6% of the drug). The vial is carefully rotated until the drug is completely dissolved.

5 ml of the finished solution is transferred to a 100 ml infusion bottle (for a dose of 100 mg, you need to take a ready-made solution from 2 vials, for a dose of 50 mg – from one bottle). The maximum concentration of the final solution for intravenous infusion should not exceed 1 mg / ml.

The color of the finished solution should be yellow or orange. If the solution has a different color or visible inclusions are detected in it, its use is not allowed.

The finished solution of Tigacil® can be stored at room temperature (no higher than 25° C) for no more than 24 hours (the finished solution – in a bottle for up to 6 hours, the remaining time – in the form of a diluted final solution).

If the storage temperature is higher than 25° C, the finished solution should be used immediately. Immediately after diluting the finished solution with 0.9% sodium chloride solution or 5% dextrose solution for injection, the final infusion solution can be stored in the refrigerator at a temperature of 2 to 8° C for no more than 48 hours.

Introduction

Tigacil® is administered intravenously through a separate infusion system or through a T-shaped catheter.

If the intravenous catheter is used for the sequential use of several medications, it should be flushed before the infusion of Tigacil® with 0.9% sodium chloride solution,5% dextrose solution for injection or Ringer’s lactate solution.

When performing the infusion, the compatibility of tigecycline and other drugs administered through the same catheter should be taken into account (see “Interaction with other drugs and other forms of interaction”).

Overdose

Not described. Intravenous use of tigecycline to healthy volunteers at a dose of 300 mg with a 60-minute duration of use led to increased nausea and vomiting. Hemodialysis does not remove tigecycline.

Special instructions

To reduce the development of resistance and ensure the effectiveness of therapy, Tigacil should be used only for the treatment and prevention of infectious diseases caused by sensitive microorganisms.

To select and correct 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 have a structural similarity to tetracycline antibiotics. Tigacil is capable of causing adverse reactions similar to those to tetracycline antibiotics.

These reactions may include increased photosensitivity, intracranial hypertension, pancreatitis, and antianabolic effects resulting in 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 show changes in liver test results during treatment with Tigacil should be monitored for timely detection of signs of liver function disorders (isolated cases of significant liver function disorders and liver failure have been reported) and to assess the benefit – risk ratio of continuing therapy with Tigacil.

The development of adverse reactions is possible after the therapy has been completed.

The efficacy 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 is observed when taking almost all antibacterial drugs, including Tigacil.

If Clostridium difficile-associated diarrhea is suspected or the diagnosis is confirmed, it may be necessary to stop using antibiotics other than those prescribed for the treatment of Clostridium difficile infection.

When using tigecycline, pseudomembranous colitis of varying severity may develop. Consideration should be given to the possibility of such a diagnosis if diarrhea occurs during or after treatment.

When prescribing Tigacil to patients with complicated intraabdominal infections due to intestinal perforation, or patients with incipient sepsis or septic shock, it is necessary to consider the feasibility of using combined antibacterial therapy.

The use of Tigacil, like any other antibiotic, can contribute to the overgrowth of non-susceptible microorganisms, including fungi. Patients should be closely monitored during treatment. When diagnosing superinfection, appropriate measures should be taken.

The effect of cholestasis on the pharmacokinetics of tigecycline has not been established. Bile excretion is approximately 50% of the total tigecycline excretion. Therefore, patients with cholestasis should be under the supervision of a doctor.

The experience of using Tigacil for the treatment of infections in patients with severe concomitant diseases is limited.

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

Use in pediatrics

The efficacy and safety of the drug in children and adolescents under 18 years of age has not been established.

Influence on the ability to drive motor vehicles and manage mechanisms

Studies of the effect of tigecycline on the ability to drive vehicles and work with mechanisms have not been conducted. Patients receiving tigecycline may experience dizziness, which may affect their ability to drive and operate machinery.

Form of production

Lyophilizate for infusion solution preparation

Storage conditions

At a temperature not exceeding 25 °C

Shelf

life 1.5 years

Active ingredient

Tigecycline

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

Adults as prescribed by a doctor

Indications

Skin Infections, Pneumonia