Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a powder or a porous mass of orange color.
1 f.
tigecycline 50 mg
[PRING] lactose monohydrate, hydrochloric acid qs to pH, sodium hydroxide qs to pH.
Vials of colorless glass with a capacity of 5 ml (10) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Antibiotic group glycilciklinov, structurally similar to tetracyclines. It inhibits protein translation in bacteria by binding to the ribosome 30S subunit and blocking the penetration of aminoacyl-tRNA molecules into the ribosome A site, which prevents the inclusion of amino acid residues in the growing peptide chains.
It is believed that tigecycline has bacteriostatic properties. At 4-fold MIC of tigecycline, the number of colonies Enterococcus spp., Staphylococcus aureus and Escherichia coli was reduced by two orders of magnitude.
The bactericidal action of tigecycline is noted for Streptococcus pneumoniae, Haemophilus influenzae and Legionella pneumophila.
The mechanism of development of sustainability
Tigecycline can overcome two main mechanisms of resistance of microorganisms observed with respect to tetracyclines: ribosomal defense and active excretion. In addition, the activity of tigecycline is not inhibited either by the action of ОІ-lactamases (including ОІ-lactamase in the extended spectrum), nor by modification of the antibiotic-sensitive areas of the bacterial membrane, either by actively removing the antibiotic from the bacterial cell or by modifying the target of the effect (eg, gyrase / topoisomerase). Thus, tigecycline has a broad spectrum of antibacterial activity. However, tigecycline does not have protection against the mechanism of resistance of microorganisms in the form of active excretion from the cell encoded by the chromosomes Proteeae and Pseudomonas aeruginosa (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 representatives of Enterobacteriaceae. In addition, some acquired resistance was found in Klebsiella pneumoniae, Enterobacter aerogenes and Enterobacter cloacae. The decreased sensitivity of the representatives of both groups to tigecycline is due to the overexpression of the gene of non-specific active excretion of AsrAb, which provides resistance to many drugs. A reduced sensitivity to tigecycline and Acinetobacter baumannii is described.
The reference values ​​of the IPC
Below are the control values ​​of the IPC established by the European Working Group on Testing for Sensitivity to Antibiotics (EUCAST).
Sensitive Resistant Pathogens
Staphylococcus spp. ? 0.5 mg / l> 0.5 mg / l
Streptococcus spp., Except S. pneumoniae? 0.25 mg / l> 0.5 mg / l
Enterococcus spp. ? 0.25 mg / l> 0.5 mg / l
Enterobacteriaceae? 1 mg / l *> 2 mg / l
Regardless of the type of pathogen? 0.25 mg / l> 0.5 mg / l
* Reduced activity of tigecycline in vitro against Proteus spp., Providencia spp. and Morganella spp.
For Acinetobacter spp., Streptococcus pneumoniae, other streptococci, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoea and Neisseria meningitidis, there is no conclusive evidence of the efficacy of tigecycline.
The effectiveness of tigecycline has been established for the treatment of intra-abdominal infections caused by anaerobic bacteria, regardless of the MIC, pharmacokinetic / pharmacodynamic parameters. Therefore, the control values ​​of the MIC are not presented. It should be noted a wide range of MIC 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 the treatment with tiogecillin of polymicrobial intra-abdominal infections is indicated.
The prevalence of acquired resistance in individual species of bacteria can vary depending on time and geographical location.
Gram-positive aerobic microorganisms are sensitive to the drug : Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis 1,2 (including strains sensitive to vancomycin), 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 agalactiae 1 , group Streptococcus anginosus 1,2 (including S.anginosus, S.intermedius and S.constellatus), Streptococcus pyogenes 1 , Streptococcus pneumoniae 3(penicillin-susceptible strains), Streptococcus pneumoniae (penicillin-resistant strains), group Streptococci viridans; Gram-negative aerobic microorganisms:Aeromonas hydrophilia, Citrobacter freundii 2 , Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae 2 , Escherichia coli 1,2 (including strains producing broad-spectrum beta-lactamase), Haemophilus influenzae 3 , Haemophilus parainfluenzae, Klebsiella oxytoca 2 , Klebsiella pneumoniae 1,2 (including strains producing ОІ-lactamase of a wide spectrum), Legionella pneumophila 3 , Moraxella catarrhalis, Serratia marcescens, Bacteroides fragilis group 1,2 , Clostridium perfringens 2 , Peptostreptococcus spp. 2 , Peptostreptococcus micros, Prevotella spp .; atypical microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae.
Species in which the acquired resistance can develop: Acinetobacter baumannii, Burkholderia cepacia, Morganella morganii, Providencia spp., Proteus spp., Stenotrophomonas maltophilia.
Microorganisms possessing their own resistance: Pseudomonas aeruginosa.
1,2,3 - species for which satisfactory activity has been demonstrated in clinical trials.
PHARMACOKINETICS
Suction
Since tigecycline is administered iv, it is characterized by 100% bioavailability.
Distribution
At concentrations of 0.1 to 1 Ојg / ml, the binding of tigecycline to plasma proteins in vitro varies from about 71% to 89%. In pharmacokinetic studies in animals and humans, it has been shown that tigecycline is rapidly distributed in tissues.
In the human body, the equilibrium V d of tigecycline is 500-700 liters (7-9 l / kg), which confirms the extensive distribution of tigecycline outside the plasma and its accumulation in tissues.
Data on the ability of tigecycline to penetrate the BBB in the human body are absent.
C ss max of tigecycline in the serum was 866 В± 233 ng / ml with 30-minute infusions and 634 В± 97 ng / ml with 60-minute infusions. AUC 0-12 hours was 2349 В± 850 ng / hr / ml.
Metabolism
On average, less than 20% of tigecycline is metabolized. The main substance found in urine and feces was unchanged tigecycline, however, glucuronide, N-acetyl metabolite, and tigecycline epimer were also detected.
Tigecycline does not inhibit 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.
Excretion
It is noted that 59% of the prescribed dose is excreted through the intestine (with most of the unchanged tigecycline entering bile), and 33% is excreted by the kidneys. Additional ways of elimination are glucuronization and excretion of unchanged tigecyclin by the kidneys.
The total clearance of tigecycline after intravenous infusion is 24 l / h. The renal clearance accounts for approximately 13% of the total clearance. Tigecycline is characterized by polyexponential withdrawal from serum, the mean terminal T 1/2 of serum after the administration of repeated doses is 42 hours, but there are significant individual differences.
Pharmacokinetics in special clinical cases
In patients with mild violations of liver function, the pharmacokinetic profile of a single dose of tigecycline does not change. However, in patients with moderate to severe hepatic impairment (class B and C on the Child-Pugh scale), 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 <30 ml / min) the pharmacokinetic profile of a single dose of tigecycline did not change, incl. and against hemodialysis.Patients with severe AUC have a 30% greater renal insufficiency than patients with normal renal function.
The pharmacokinetics of tigecycline in elderly patients, in general, did not differ from other age groups.
The pharmacokinetics of tigecycline in patients under the age of 18 years have not been studied.
Clinically significant differences in the clearance of tigecycline in men and women are not established.
The clearance of tigecycline does not depend on the race.
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 with a body weight of more than 125 kg, the AUC value was 25% lower. Data on patients with a body weight of more than 140 kg are absent.
INDICATIONS
- complicated skin and soft tissue infections;
- complicated intra-abdominal infections;
- Community-acquired pneumonia.
DOSING MODE
The drug is injected intravenously into the drip for 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, with community-acquired pneumonia - 7-14 days.
The duration of treatment is determined by the severity and localization of the infection and the clinical response of the patient to treatment.
Patients with mild and moderate hepatic impairment (Class A and B on the Child-Pugh scale) do not require a dose adjustment. Patients with severe hepatic insufficiency (class C on the Child-Pugh scale) after the initial dose of Tigacil 100 mg, then the drug is prescribed at 25 mg every 12 hours; and care must be taken to monitor the patient's response to treatment.
Patients with renal insufficiency and patients on hemodialysis do not need a dose adjustment.
Older patients do not need a dose adjustment.
Rules for the preparation and administration of an infusion solution
Before use, dissolve the contents of each Tigacil vial in a 0.9% sodium chloride solution, 5% dextrose injection solution or Ringer's lactate solution in an amount of 5.3 ml to obtain a ready solution with a tigecycline concentration of 10 mg / ml (5 ml of the prepared solution contains 50 mg of tigecycline, each vial contains an excess of 6%). The bottle is gently rotated until the drug is completely dissolved.
5 ml of the finished solution is transferred to a vial with a solution for infusion with a capacity of 100 ml (for a dose of 100 mg, it is necessary to take a ready solution of 2 bottles, for a dose of 50 mg - from 1 bottle). The maximum concentration of the final solution for intravenous infusion should not exceed 1 mg / ml. The color of the finished solution must be yellow or orange. If the solution has a different color or the visible inclusions are determined, its use is not allowed. The ready-made Tigacil solution can be stored at room temperature for no more than 24 hours (ready-made solution in a vial for up to 6 hours, remaining time in the form of a diluted final solution). Immediately after dilution of the finished solution, the final infusion solution can be stored in the refrigerator at a temperature of 2 В° to 8 В° C not more than 48 hours.
Introduction. Tigacil should be administered iv in a separate infusion system or through a T-shaped catheter. If an I / O catheter is used for the sequential administration of several drugs, it must be rinsed before infusion of Tigacil with 0.9% sodium chloride solution, 5% dextrose solution for injection or Ringer's lactate solution. When carrying out the infusion, the compatibility of tigecycline and other drugs administered through a single catheter should be considered.
SIDE EFFECT
Most often: nausea (26%) and vomiting (18%), which usually occur at the beginning of treatment (on days 1 or 2 of treatment) and, in most cases, have a light or medium-heavy course. The reason for stopping Tigacil therapy was most often nausea (1%) and vomiting.
Classification of side effects: very often (? 1/10); often (from? 1/100 to <1/10); sometimes (from? 1/1000 to <1/100); rarely (from? 1/10 000 to <1/1000); very rarely (? 1 / 10,000), single cases (spontaneous post-marketing messages).
From the coagulation system: often - an increase in APTT, prothrombin time / MHO.
From the hemopoietic 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 ACT and ALT in the serum, hyperbilirubinemia; sometimes jaundice; in isolated cases - pronounced violations of the liver and hepatic insufficiency.
Dermatological reactions: often - itching, rash.
On the part of 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 healing of wounds; sometimes - chills.
On the part of laboratory indicators: often - increased blood urea nitrogen, increased serum AF activity, increased activity of amylase in the serum, hypoproteinemia;sometimes - an increase in creatinine in the blood, hypocalcemia, hyponatremia, hypoglycemia.
CONTRAINDICATIONS
- hypersensitivity to the components of the drug;
- Hypersensitivity to antibiotics of the tetracycline group.
With caution should be used in severe hepatic insufficiency.
PREGNANCY AND LACTATION
In pregnancy, the use of Tigacil is permissible only in case of emergency, when the benefit to the mother exceeds the possible risk to the fetus.
Data on the excretion of tigecycline with human milk are absent. If it is necessary to administer tigecycline during lactation, breastfeeding should be discontinued.
Experience in the use of the drug Tigacil during childbirth is not available.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Patients with mild and moderate hepatic impairment (Class A and B on the Child-Pugh scale) do not require a dose adjustment. Patients with severe hepatic insufficiency (class C on the Child-Pugh scale) after the initial dose of Tigacil 100 mg, then the drug is prescribed at 25 mg every 12 hours; and care must be taken to monitor the patient's response to treatment.
APPLICATION FOR CHILDREN
The efficacy and safety of the drug in children and adolescents under the age of 18 years is not established.
APPLICATION IN ELDERLY PATIENTS
Older patients do not need a dose adjustment.
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 correct antibacterial therapy, if possible, microbiological identification of the pathogen should be made and its sensitivity to tigecycline determined. Tigacil can be used for empirical antibiotic monotherapy before the results of microbiological tests are obtained.
Antibiotics belonging to the class of glycylcyclines have a structural similarity with antibiotics of the class of tetracyclines. Tigacil is able to cause adverse reactions similar to adverse reactions to antibiotics of the tetracycline class. Such reactions can be increased photosensitivity, intracranial hypertension, pancreatitis and anti-anabolic effect, leading to an increase in urea nitrogen in the blood, azotemia, acidosis and hypophosphatemia. Therefore, Tigacil should be used with caution in patients with a known sensitivity to tetracycline antibiotics.
Anaphylactic / anaphylactoid reactions, incl. anaphylactic shock, are noted when almost all antibacterial agents are used, including Tigacil.
Patients who experience changes in liver test results should be monitored for the timely detection of signs of liver dysfunction (single cases of significant violations of liver function and hepatic insufficiency) and an assessment of the relationship between the benefit and risk 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 pneumonia has not been confirmed by the results of clinical studies.
Diarrhea associated with Clostridium difficile has been observed with almost all antibacterial drugs, including Tigacil. If you suspect a diarrhea associated with Clostridium difficile or confirmation of this diagnosis, you may need to stop using antibiotics other than those prescribed for the treatment of an infection caused by Clostridium difficile.
When tigecycline is used, it is possible to develop pseudomembranous colitis of varying severity. It is necessary to consider the possibility of such a diagnosis in the event of diarrhea occurring during or after the completion of treatment.
When appointing Tigacil, patients with complicated intra-abdominal infections due to perforation of the intestine, or patients with sepsis or septic shock, should consider the advisability of using combination antibacterial therapy.
The use of Tigacil, like any other antibiotic, can promote the excessive growth of non-susceptible microorganisms, including fungi. During treatment, patients should be closely monitored. When diagnosing superinfection, appropriate measures should be taken.
The effect of cholestasis on the pharmacokinetics of tigecycline has not been established. The excretion of the bile is approximately 50% of the total excretion of tigecycline. Therefore, patients with cholestasis should be under a doctor's supervision.
Experience Tigatsila use to treat infections in patients with severe concomitant diseases is limited.
Application Tigatsila during tooth formation can lead to discoloration of teeth to yellow, gray, brown. Tigatsil not be used during tooth development except for the cases when other drugs are not effective or are contraindicated.
Use in Pediatrics
The efficacy and safety of the drug in children and adolescents under the age of 18 years has not been established.
Impact on the ability to drive vehicles and manage mechanisms
Studies of tigecycline effects on the ability to transport management and operation mechanisms have not been conducted. In patients receiving tigecycline and may cause dizziness, which could affect the ability to drive and operate machinery.
OVERDOSE
Overdosing Tigatsila preparation is not described.
B / in a tigecycline to healthy volunteers at a dose of 300 mg at 60-minute duration of administration resulted in frequent nausea and vomiting.
Hemodialysis not provide tigecycline excretion from the body.
DRUG INTERACTION
When concomitant use Tigatsila and warfarin (in a single dose 25 mg) was observed decrease in clearance of R-warfarin and S-warfarin by 40% and 23% decrease in AUC warfarin by 68% and 29% respectively. The mechanism of this interaction has not yet been installed. Because tigecycline is able to increase both the prothrombin time / INR and APTT, while applying Tigatsila simultaneously with anticoagulants should be closely monitored for the results of the relevant coagulation tests. Warfarin does not alter the pharmacokinetic profile Tigatsila.
Tigecycline is not metabolized by the cytochrome P450 isoenzyme system. It is therefore expected that the active agents that inhibit or induce the activity of isoenzymes of cytochrome P450 system will not change the clearance Tigatsila. In turn Tigatsil hardly affects the metabolism of said groups of medicinal compounds.
Tigatsil at the recommended dosage does not influence the rate and extent of absorption or clearance of digoxin (500 g, followed by the appointment in a daily dose of 250 mg). Digoxin does not alter the pharmacokinetic profile of tigecycline. Therefore, when used in conjunction with digoxin Tigatsila dose adjustment is required.
In the application of antibiotics simultaneously with oral contraceptives contraceptive effectiveness may decrease.
In in vitro studies antagonism between tigecycline and other antibiotics belonging to the commonly used classes, was not observed.
Compatibility
Tigatsil compatible with 0.9% sodium chloride solution, 5% dextrose solution for injection or Ringer lactate solution. In the appointment through the T-shaped catheter Tigatsil dissolved in 0.9% sodium chloride or 5% dextrose solution for injection is compatible with amikacin, dobutamine, dopamine hydrochloride, gentamicin, haloperidol, Ringer's lactate, lidocaine hydrochloride, metoclopramide, morphine, norepinephrine, piperacillin / tazobactam (dosage form containing EDTA), potassium chloride, propofol, ranitidine hydrochloride, theophylline, and tobramycin.
Incompatibility
When applied through the T-shaped catheter Tigatsil incompatible with amphotericin B, liposomal amphotericin B, diazepam, esomeprazole and omeprazole.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 1.5 years.
