Tigacil, lyophilizate 50 mg 10 pcs

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

Tigecycline is believed to have bacteriostatic properties. A 4-fold MPC of tigecycline resulted in a two orders of magnitude decrease in the number of colonies of Enterococcus spp., Staphylococcus aureus and Escherichia coli.

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

The mechanism of resistance development

Tigecycline can overcome the two main mechanisms of resistance of microorganisms observed against tetracyclines: ribosomal protection and active excretion.

In addition, tigecycline activity is not inhibited by the action of β-lactamases (including extended spectrum β-lactamases), nor by modification of bacterial membrane sites sensitive to the antibiotic, nor by active excretion of the antibiotic from the bacterial cell or by modification of the target of action (e.g. gyrase/topoisomerase).

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

Decreased sensitivity of representatives of both groups to tigecycline is caused by overexpression of the gene of nonspecific active excretion of AsgAV, which provides resistance to many drugs. Acinetobacter baumannii has also been described to be hypersensitive to tigecycline.

The IPC reference values

The following are the IPC reference values established by the European Working Group on Antibiotic Susceptibility Testing (EUCAST).

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

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

The efficacy of tigecycline for the treatment of intraabdominal infections caused by anaerobic bacteria has been established regardless of MPC, pharmacokinetic/pharmacodynamic parameters. Therefore, control MPK values are not presented.

We should note the wide range of MPC of tigecycline for Bacteroides spp. and Clostridium spp., 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 intra-abdominal infections has been shown.

The prevalence of acquired resistance in individual bacterial species may vary with time and geographic location.

The Gram-positive aerobic microorganisms are sensitive to the drug:

Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis^1,2 (including vancomycin-sensitive strains), Enterococcus faecalis (including vancomycin-resistant strains), Enterococcus gallinarum, Staphylococcus aureus^1,2 (including methicillin-sensitive and resistant strains), Staphylococcus epidermidis (including methicillin-sensitive and resistant strains), Staphylococcus haemolyticus, Streptococcus agalactiae¹,Streptococcus anginosus group^1,2 (including S.anginosus, S.intermedius, and S.constellatus), Streptococcus pyogenes¹,Streptococcus pneumoniae³ (penicillin-sensitive strains), Streptococcus pneumoniae (penicillin-resistant strains), Streptococci viridans group;

Gram-negative aerobic microorganisms: Aeromonas hydrophilia, Citrobacter freundii², Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae², Escherichia coli^1,2 (including broad-spectrum beta-lactamase-producing strains), Haemophilus influenzae³, Haemophilus parainfluenzae, Klebsiella oxytoca², Klebsiella pneumoniae^1,2 (including strains producing broad-spectrum β-lactamase), Legionella pneumophila³,Moraxella catarrhalis, Serratia marcescens, Bacteroides fragilis group^1,2,Clostridium perfringens²,Peptostreptococcus spp.²,Peptostreptococcus micros, Prevotella spp.; atypical microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae.

Species with possible development of acquired resistance: Acinetobacter baumannii, Burkholderia cepacia, Morganella morganii, Providencia spp., Proteus spp., Stenotrophomonas maltophilia.

Microorganisms with intrinsic resistance: Pseudomonas aeruginosa.

^1,2,3 -species against which satisfactory activity has been demonstrated in clinical trials.

Pharmacokinetics

Intake

Since tigecycline is administered intravenously, it has 100% bioavailability.

Distribution

At concentrations of 0.1 to 1 µg/ml, the binding of tigecycline to plasma proteinsin vitro ranges from approximately 71% to 89%. In pharmacokinetic studies in animals and humans it has been shown that tigecycline is rapidly distributed in tissues.

In humans, the equilibrium V_d tigecycline is 500-700 L (7-9 L/kg), confirming the extensive distribution of tigecycline outside the plasma and its accumulation in tissues.

There are no data on the ability of tigecycline to penetrate through the BBB in humans.

The C_ss^max tigecycline in serum was 866±233 ng/mL with 30-minute infusions and 634±97 ng/mL with 60-minute infusions. The AUC_{0-12 h} was 2349±850 ng×hour/mL.

Metabolism

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

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

Elimation

It has been observed that 59% of the administered 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 excretion are 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 excretion from serum; the mean terminal T_1/2 from serum after repeated doses is 42 hours, but significant individual differences are observed.

Pharmacokinetics in Special Clinical Cases

The pharmacokinetic profile of single-dose tigecycline is not altered in patients with mild hepatic impairment.

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

In patients with renal impairment (QC)

The pharmacokinetics of tigecycline in elderly patients were generally not different from other age groups.

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

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

The clearance of tigecycline is independent of race.

Clearance, including normalized by body weight, and AUC did not differ markedly in patients with different body weights, including those exceeding 125 kg. In patients with body weight more than 125 kg the AUC value was 25% lower. No data were available for patients with a body weight greater than 140 kg.

Indications

Active ingredient

Composition

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

auxiliary substances:

How to take, the dosage

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

The course of treatment:

– for complicated skin and soft tissue infections and complicated intra-abdominal infections 5-14 days.
– for community-acquired pneumonia – 7-14 days.

The duration of treatment is determined by the severity and localization of the infection and the patient’s clinical response to treatment.

Hepatic failure

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

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

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

Renal impairment
Patients with renal impairment and patients on hemodialysis do not require dose adjustment.

Elderly patients
Dose adjustment is not required.

Periatric use
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 experienced in the treatment of infectious diseases. Tigecycline should not be used in children younger than 8 years of age due to insufficient data on the effectiveness and safety of the drug in this group, as well as due to changes in the color of teeth (see section “Cautions”).

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

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

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

Instructions for preparing the solution and administering the drug

Preparation

Before use, the contents of each vial of Tigacycline® should be diluted 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-to-use solution with a concentration of 10 mg/ml of tigecycline.

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

5 ml of ready-to-use solution is transferred to a 100 ml infusion solution vial (for 100 mg dose the ready-to-use solution must be taken from 2 vials, for 50 mg dose – from one vial). The maximum concentration of the final solution for intravenous infusion should not exceed 1 mg/ml.

The color of the final solution should be yellow or orange. If the solution has a different color or if visible inclusions are detected, the solution should not be used.

The ready solution of Tigacil® drug can be stored at room temperature (not exceeding 25 ° C) for no more than 24 hours (ready solution in a bottle up to 6 hours, the remaining time in the form of diluted final solution).

In case the storage temperature is above 25 ° C the ready solution should be used immediately. Immediately after dilution of the finished solution with 0.9% sodium chloride solution or 5% dextrose solution for injection, the final solution for infusion may be stored in the refrigerator at 2 to 8° C for not more than 48 hours.

Injection

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

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

When administering the infusion, the compatibility of tigecycline and other drugs administered through the same catheter should be considered (see “Interaction with other medicinal products and other forms of interaction”).

Interaction

Compatibility

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

. When administered through a T-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 ethylenediaminetetetraacetate – EDTA), potassium chloride, propofol, ranitidine, theophylline and tobramycin.

Incompatibilities

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

Warfarin

When concomitant use of Tigacil® and warfarin (single dose of 25 mg) there is a decrease in clearance of R-warfarin and S-warfarin of 40% and 23%, and an increase in AUC of warfarin of 68% and 29%, respectively.

The mechanism of this interaction has not yet been established. Since tigecycline may prolong both PV/ INR and ACTV, when using Tigacil® simultaneously with anticoagulants, the results of the corresponding coagulation tests should be closely monitored.

Warfarin does not alter the pharmacokinetic profile of tigecycline.

Inhibitors or inducers of cytochrome P450 isoenzymes

Tigecycline is not metabolized via cytochrome P450 isoenzymes. Therefore, active substances that inhibit or induce the activity of cytochrome P450 isoenzymes are not expected to alter the clearance of tigecycline.

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

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 extent 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, no dose adjustment is required when using Tigacil® together with digoxin.

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

The oral contraceptives

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

In in vitro studies, antagonism between tigecycline and other antibiotics belonging to commonly used classes has not been observed.

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 susceptible microorganisms.

To select and adjust antibiotic therapy, if possible, microbiological identification of the pathogen and determination of its sensitivity to Tigacycline should be carried out. Tigacycline may be used for empirical antibiotic monotherapy until the results of microbiological tests are available.

The antibiotics belonging to the glycylcycline class have structural similarities with antibiotics of the tetracycline class. Tigacil is capable of causing adverse reactions similar to adverse reactions to antibiotics of the tetracycline class.

These reactions may include increased photosensitivity, intracranial hypertension, pancreatitis, and anti-anabolic effects resulting in increased blood urea nitrogen, azotemia, acidosis, and hypophosphatemia.

Tigacil should therefore be used with caution in patients with known sensitivity to tetracycline antibiotics.

Anaphylactic/anaphylactoid reactions, including anaphylactic shock, have been reported with virtually all antibacterial agents, including Tigacil.

Patients in whom during treatment with Tigacil changes in hepatic test results are observed should be observed for timely detection of signs of liver dysfunction (single cases of significant liver dysfunction and liver failure have been registered) and assessment of 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 hospitalized pneumonia has not been confirmed by the results of clinical trials.

Diarrhea associated with Clostridium difficile has been noted with almost all antibacterial drugs, including Tigacil.

If diarrhea associated with Clostridium difficile is suspected or confirmed, discontinuation of antibiotics other than those prescribed to treat infection with Clostridium difficile may be necessary.

When using tigecycline, pseudomembranous colitis of varying severity may develop. It is necessary to consider the possibility of this diagnosis in case of diarrhea 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 feasibility of combined antibiotic therapy should always be considered.

The use of Tigacil, like any other antibiotic, may promote overgrowth of non-susceptible microorganisms, including fungi. Patients should be closely monitored during treatment. Appropriate measures should be taken if superinfection is diagnosed.

The effect of cholestasis on the pharmacokinetics of tigecycline has not been established. Excretion with bile is approximately 50% of the total excretion of tigecycline. Therefore, patients with cholestasis should be monitored by a physician.

Tigacycline has limited experience in the treatment of infections in patients with severe comorbidities.

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

Pediatric use

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

Impact on driving and operating machinery

Tigecycline has not been studied on the ability to drive and operate vehicles. Patients receiving tigecycline may experience dizziness, which may affect driving and operating machinery.

Contraindications

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

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

Side effects

Side effects are presented by organ and system in the classification: very common (≥1/10); common (≥1/100 to <1/10); infrequent (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (≤1/10000), isolated cases (spontaneous post-marketing reports).

Blood system and hematopoietic organs:

Immune system disorders:

Nervous system disorders:

Cardiovascular system:

Gastrointestinal tract:

Hepatobiliary system disorders:

Skin and subcutaneous fat

Urogenital system disorders:

General and injection site reactions:

Laboratory parameters:

Respiratory system disorders:

Reactions characteristic of antibiotics: pseudomembranous colitis.

*Elevations of ALT and AST activity were observed more frequently after the end of therapy with Tigacil®.

The pooled analysis of clinical data from 13 phase 3 and 4 studies of Tigacil® for registered and unregistered indications found greater overall mortality (i.e., death from any cause, including non-treatment-related causes) in patients with severe infections who received Tigacil®.

The overall mortality in patients receiving Tigacil® was 4% (150/3788), comparison drugs was 3% (110/3646), and the relative risk difference for mortality was 0.6% (confidence interval (CI): 0,1 – 1,2).

The reasons for increased overall mortality in patients receiving Tigacil® have not been identified. In general, lethal outcomes were the result of worsening of the course of infection, complications of infection or comorbidities.

Children
Data on the use of tigecycline in children are limited to two pharmacokinetic studies and one open clinical trial 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, single-dose escalation pharmacokinetic study, the safety of tigecycline was examined in 25 pediatric patients (8 to 16 years old) who had recently had an infectious disease.

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

The safety of tigecycline was also investigated in 58 pediatric 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 side effect profile in these 58 patients was similar to that of adults, except for nausea (48.3%), vomiting (46.6%), and increased plasma lipase levels (6.9%), which occurred more frequently in children than in adults.

Pregnancy use

In pregnancy, the use of Tigacycline is allowed only in case of extreme necessity, when the benefit to the mother outweighs the possible risk to the fetus.

The data on excretion of tigecycline with breast milk in humans are not available.

If it is necessary to prescribe tigecycline during lactation, breastfeeding should be stopped. There is no experience of using the drug Tigacycline during childbirth.