Tigacil® (Tigacil)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTigecyclineTigecycline
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  • Tigacil®
    lyophilizate
    Pfizer Inc.     USA
  • Tigecycline J
    lyophilizate d / infusion 
    JODAS EKSPOIM, LLC     Russia
    • Dosage form: & nbsplyophilizate for solution for infusion
    Composition:
    One bottle contains:
    active substance: tigecycline 50 mg;
    auxiliary substances: lactose monohydrate 100 mg, hydrochloric acid q.s. to pH, sodium hydroxide q.s. up to pH.

    Description:Orange lyophilized powder or porous mass.
    Pharmacotherapeutic group:Antibiotic-tetracycline
    ATX: & nbsp

    J.01.A.A.12   Tigecycline

    Pharmacodynamics:
    Mechanism of action
    Antibiotic tigecycline belongs to the class of glycylcyclines, structurally similar to tetracyclines. It inhibits protein translation in bacteria by binding to the 30S subunit of the ribosome and blocking the penetration of aminoacyl-tRNA molecules into the A site of the ribosome, which prevents the inclusion of amino acid residues in the growing peptide chains.
    It is believed that tigecycline has bacteriostatic properties. At 4-fold minimal inhibitory concentration (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 beta-lactamases (including beta-lactamase extended spectrum) nor by modification
    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). In this way, 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 Proteae chromosomes (see below) and Pseudomonas aeruginosa (MexXY-OprM outflow system). There is no cross-resistance between tigecycline and most classes of antibiotics.
    In general, microorganisms belonging to the Proteae family (.Proteus spp., Providencia spp., And Morganella spp.) Are less susceptible to tigecycline than other representatives of Enterobacteriaceae. In addition, some acquired resistance was found in Klebsiella pneumoniae, Enterobacter aerogenes and Enterobacter cloacae.Reduced sensitivity of both groups to tigecycline is due to overexpression of the gene of non-specific active excretion of AsgAB, 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).
    Staphylococcus spp. S <0.5 mg / l and R> 0.5 mg / l (S-sensitive, R-resistant) Streptococcus spp., Except for S. pneumoniae S <0.25 mg / l and R> 0.5 mg / l Enterococcus spp. S <0.25 mg / l and R> 0.5 mg / l Enterobacteriaceae S <1 (L) mg / l and R> 2 mg / l.
    Regardless of the type of pathogen S <0.25 mg / l and R> 0.5 mg / l.
    (L) There was a decreased activity of tigecycline in vitro against Proteus, Providencia and Morganella spp.
    For Acinetobacter, Streptococcus pneumoniae, other streptococci, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoea and Neisseria meningitidis, there is no conclusive evidence of the efficacy of tigecycline.
    Tigecycline has proved effective in the treatment of intra-abdominal infections caused by anaerobic bacteria, regardless of the MIC, pharmacokinetic / pharmacodynamic parameters. In connection with the above, the control values ​​of the IPC are not presented. It should be noted a wide range of MPC tigecycline for microorganisms belonging to the genera Bacteroides and Clostridium, 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.
    Sensitivity
    The prevalence of acquired resistance in individual species of bacteria can vary depending on time and geographical location.


    Sensitivity of microorganisms to tigecycline
    Gram-positive aerobes;
    Enterococcus spp. +
    Enterococcus avium
    Enterococcus casseliflavus
    Enterococcus faecalis1,2 (including strains sensitive to vancomycin)
    Enterococcus faecalis (including strains resistant to vancomycin)
    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 aneinosus 1,2 (including S. anginosus, S. intermedius and S. constellatus)
    Streptococcus pyogenes1
    Streptococcus pneumoniae3 (penicillin-sensitive strains)
    Streptococcus pneumoniae (penicillin-resistant strains)
    Group Streptococci viridans
    Gram-negative aerobes;
    Aeromonas hvdrophilia
    Citrobacter ffeundii 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 oxvtoca2
    Klebsiella pneumoniae 1,2 (including strains producing broad-spectrum beta-lactamase)
    Legionella pneumophila3
    Moraxella catarrhalis
    Serratia marcescens
    Bacteroides fragilis group + 1,2
    Clostridium perfringens + 2
    Peptostreptococcus spp. +2
    Peptostreptococcus micros
    Prevotella spp.
    Atypical microorganisms
    Mycoplasma pneumoniae ++
    Chlamvdiapneumoniae +
    Types that can develop acquired stability
    Acinetobacter baumannii
    Burkholderia cepacia
    Morganella morganii
    Providencia spp.
    Proteus spp.
    Stenotrophomonas maltophilia
    Microorganisms possessing their own resistance
    Pseudomonas aeruginosa
    1,2,3 species, in relation to which satisfactory activity was demonstrated in clinical studies
    + see the section "Pharmacodynamics" above.
    ++ serology

    Pharmacokinetics:
    Suction
    Because the tigecycline injected intravenously, it is characterized by 100% bioavailability. Distribution
    At concentrations ranging from 0.1 to 1.0 μg / ml, the binding of tigecycline to plasma proteins in vitro ranged from about 71% to about 89%. In pharmacokinetic studies in animals and humans, it has been shown that tigecycline quickly distributed in tissues.
    In the human body, the equilibrium volume of tigecycline distribution was from 500 to 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 blood-brain barrier in the human body are absent.
    The equilibrium maximum concentration (Cssmax) of tigecycline in the serum was 866 ± 233 ng / ml with 30-minute infusions and 634 ± 97 ng / ml with 60-minute infusions.The area under the concentration-time curve (AUQ0-124 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, however, glucuronide, N-acetyl metabolite, and tigecycline epimer were also detected.
    Tigecycline does not inhibit metabolism mediated by the following six isoforms of cytochrome CYP: 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4. It is neither a competitive inhibitor nor an irreversible inhibitor of cytochrome P 450.
    Excretion
    It is noted that 59% of the prescribed dose is excreted through the intestine (with most of the unchanged tigecycline coming in bile), and 33% is excreted by the kidneys. Additional ways of excretion are glucuronidation 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 characterized by polyexponential withdrawal from serum, the average terminal half-life of serum after the appointment of repeated doses is 42 hours, but there are significant individual differences.
    Liver failure
    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 according to the Child-Pugh classification), total clearance of tigecycline was reduced by 25% and 55%, and the elimination half-life was increased by 23% and 43%, respectively.
    Renal insufficiency
    In patients with renal insufficiency (creatinine clearance <30 ml / min), the pharmacokinetic profile of a single dose of tigecycline did not change, including against the background of hemodialysis. In patients with severe renal insufficiency, AUC was 30% greater than in patients with normal renal function.
    Elderly patients
    The pharmacokinetics of tigecycline in the elderly, in general, did not differ from other age groups.
    Children
    The pharmacokinetics of tigecycline in patients under the age of 18 years have not been studied.
    Floor
    Clinically significant differences in the clearance of tigecycline in men and women are not established.
    Race
    The clearance of tigecycline does not depend on the race.
    The weight
    The clearance, including normalized by body weight, and AUC did not differ significantly in patients with different body weight, including those exceeding 125 kg.In patients with a body weight of more than 125 kg, the AU 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 tissues, with the exception of infections with syndrome of diabetic foot. \

    - Complicated intra-abdominal infection.

    - Extramarital pneumonia. '-

    Contraindications:
    Hypersensitivity to any of the components of the drug or to antibiotics of the class of tetracyclines.

    Carefully:
    Severe hepatic impairment

    Pregnancy and lactation:
    During 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.
    There are no data on the intake of tigecycline in human milk. If it is necessary to administer tigecycline during lactation, breastfeeding should be discontinued.
    Experience in the appointment of the drug Tigacil during childbirth is not present.
    APPLICATION FOR CHILDREN
    Efficacy and safety in children under 18 years of age is not established.

    Dosing and Administration:
    Intravenously, drip for 30-60 minutes (see "Instructions for preparing the solution and administering the drug").
    The initial dose for adults is 100 mg, then 50 mg every 12 hours.
    A course of treatment:
    - with complicated infections of the skin and soft tissues, as well as complicated intra-abdominal infections 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.
    Liver failure
    Patients with mild to moderate hepatic impairment (Child-Pugh class A and B classes) do not require dose adjustment.
    Patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) after the initial dose of Tigacil 100 mg, then the drug is prescribed 25 mg every 12 hours; at the same time, care must be taken to monitor the patients' response to treatment.
    Renal insufficiency
    Patients with renal insufficiency and patients on hemodialysis do not need a dose adjustment.
    Elderly patients No dose adjustment is required.
    Instructions for preparing the solution and administering the preparation
    Preparation
    Before use, dilute the contents of each Tigacil vial with 0.9% sodium chloride solution,5% dextrose injection solution or Ringer's lactate solution in an amount of 5.3 ml to obtain a final solution with a tigecycline concentration of 10 mg / ml. (Note: 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 prepared 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 from 2 vials, for a dose of 50 mg - from one vial). 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 solution - in the 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 solution for infusion may be stored in the refrigerator at a temperature of 2 to 8 ° C for not more than 48 hours.
    Introduction
    Tigacil is administered intravenously via a separate infusion system or via a T-shaped catheter.If the intravenous catheter is used for the sequential administration of several drugs, it must be rinsed before Tigacil infusion with 0.9% sodium chloride solution, 5% dextrose injection solution or Ringer lactate solution. During the infusion, the compatibility of tigecycline and other drugs administered through a single catheter (see "Interaction with other drugs and other forms of interaction") should be considered,

    Side effects:

    The most common nausea (26%) and vomiting (18%), which are usually occur at the beginning of treatment (at the first or second day of treatment) and, in most cases, of cases have a mild or moderate flow. In most cases. cases These adverse reactions develop in the early stages of treatment (1-2 day).

    PThe main reason for stopping Tigacil therapy was nausea (1%) and vomiting (1%).

    Side effects are presented by organs and systems in the classification: very often (> 1/10);

    often (from> 1/100 to <1/10); infrequently (from> 1/1000 to <1/100); rarely (from> 1/10000 to <1/1000); very rarely (<1/10000), isolated cases (spontaneous post-marketing messages).

    On the part of the blood system and hemopoiesis:

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

    Infrequently: eosinophilia, an increase in the international normalized relationship (INR).

    Single cases: thrombocytopenia.

    From the immune system:

    Single cases anaphylactic / anaphylactoid reaction.

    From the nervous system:

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

    From the cardiovascular system:

    Often: phlebitis.

    Infrequently: thrombophlebitis.

    From the gastrointestinal side tract:

    Often: nausea, vomiting, diarrhea.

    Often: abdominal pain, indigestion, anorexia.

    Infrequently: acute pancreatitis.

    From the hepatobiliary system:

    Often: increased activity aspartate aminotransferase (ACT) - at serum *, increased activity alanine aminotransferase (ALT) in serum *, hyperbilirubinemia.

    Infrequently: jaundice.

    Single cases: pronounced violations liver function and hepatic insufficiency, cholestasis.

    From the skin and subcutaneous fat cellulose

    Often: itching, rash.

    Single cases: severe dermal reactions, including Stevens- Johnson.

    From the genitourinary system:

    Infrequently: vaginal candidiasis, vaginitis, leucorrhea.

    General reactions and reactions at the site of administration:

    Often: asthenia, delayed healing wounds, abscess, infection.

    Infrequently: inflammation, pain, swelling and phlebitis in injection site, chills, septic shock, allergic reactions.

    Labortion indicators:

    Often: increased blood urea nitrogen, increased activity of alkaline phosphatase in the serum, activity of amylase in the serum, hypoproteinemia.

    Infrequently: increase in creatinine in the blood, hypocalcemia hyponatremia, hypoglycemia.

    From the respiratory system: Often: pneumonia.

    * increased ALT activity and ' ACT noted more often after the end of therapy with Tigacil.

    Overdose:
    Not described. Intravenous administration of tigecycline to healthy volunteers at a dose of 300 mg with a 60 minute duration of administration resulted in increased nausea and vomiting. Hemodialysis does not provide the removal of tigecycline.

    Interaction:
    Compatibility / incompatibility with drugs and solvents with simultaneous administration
    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 a 0.9% solution of sodium chloride or a 5% solution of dextrose for injection is compatible with amikacin, dobutamine, dopamine hydrochloride, gentamycin, haloperidol, Ringer's lactate solution, lidocaine hydrochloride, metoclopramide, morphine, norepinephrine, piperacillin / tazobactam (form containing ethylenediaminetetraacetate-EDTA), potassium chloride, propofol, ranitidine hydrochloride, theophylline and tobramycin.
    Incompatibility
    When applied via a T-shaped catheter, Tigacil is incompatible with amphotericin B, amphotericin B liposomal, diazepam, esomeprazole, and omeprazole.
    Warfarin
    With the concomitant use of Tigacil and warfarin (a single dose of 25 mg), the clearance of R-warfarin and S-warfarin is reduced by 40% and 23%, and Warfarin AUC by 68% and 29%, respectively. The mechanism of such interaction to the present
    time is not set. Because the tigecycline can extend both PV / INR and APTT, when using Tigacil simultaneously with anticoagulants, it is necessary to closely monitor the results of the corresponding coagulation samples. Warfarin does not change the pharmacokinetic profile of Tigacil.
    Inhibitors or inducers of cytochrome P450 isoenzymes
    Tigecycline is not metabolized by cytochrome P450 isoenzymes. Therefore, it is expected that active substances that suppress or induce the activity of cytochrome P450 isoenzymes will not change the Tigacil clearance. In turn, Tigacil is unlikely to affect the metabolism of these groups of drug compounds.
    Digoxin
    Tigacil in 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 change the pharmacokinetic profile of tigecycline. Therefore, when Tigacil is used together with digoxin, dose adjustment is not required.
    Oral contraceptives
    When using antibiotics simultaneously with oral contraceptives, the effectiveness of contraceptives may decrease.
    In in vitro studies, antagonism between tigecycline and other antibiotics belonging to frequently used classes was not observed.

    Special instructions:

    In order to reduce the development of resistance and ensure the effectiveness of therapy,use Tigacil only for the treatment and prevention of infectious diseases, caused by microorganisms that are sensitive to preparation:

    To select and correct antibacterial therapy, whenever possible, microbiological identification of the pathogen and determine its sensitivity to tigecycline. Tigacil can be used for empirical antibiotic monotherapy before the results, microbiological tests.

    Antibiotics belonging to the class of glycylcyclines have a structural similarity with antibiotics of the class of tetracyclines. Tigacil can cause adverse reactions, / similar to adverse reactions on antibiotics of the tetracycline class. Such reactions can be increased photosensitivity, intracranial hypertension, pancreatitis and anti-anabolic agentswhich leads to an increase in the content of 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 noted when using almost all antibacterial agents, including Tigacil.

    Patients who, when treated with Tigacil, are experiencing changes in the results of liver tests, should be observed for a timely revealing signs of liver function abnormalities - (single cases of significant violations of liver function and hepatic insufficiency) and an evaluation of the benefit ratio. and the risk of continued therapy with Tigacil.

    Unwanted reactions can develop after the therapy was completed.

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

    Diarrhea of ​​different severity, associated with Clostridium difficile, It was noted when practically all antibacterial drugs were taken, including Tigacil. It is necessary to consider the possibility of such a diagnosis in the event of diarrhea occurring during or after the completion of treatment. If you suspect a diarrhea associated with Clostridium difficile, or confirmation of this diagnosis, it may be necessary to stop using antibiotics other than those prescribed for the treatment of infection caused by Clostridium difficile.

    When Tigacil is prescribed to patients with complicated intra-abdominal infections, due to perforation of the intestine, or to patients with developing sepsis or septic shock, it is necessary to consider the advisability of using a combined antibacterial therapy.

    The use of Tigacil, like any other antibiotic, may contribute to the excessive growth of non-responsive microorganisms, including fungi. During treatment, patients should be closely monitored. When diagnosing superinfection, one should take appropriate measures.

    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 under the supervision of a doctor.

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

    The use of Tigacil during the formation of teeth can lead to a discoloration of the teeth in yellow, gray, brown. Tigacil should not be used during the period of development of the teeth, except when other drugs are not effective or contraindicated.

    There are reports of the development of acute pancreatitis with Tigacil, in some cases fatal. Caution should be exercised when using Tigacil in patients with suspected acute pancreatitis (clinical symptoms or corresponding changes in laboratory indicators). It is known about cases of development acute pancreatitis in patients who did not have risk factors for the development of the disease. Usually the symptoms of pancreatitis disappear after the drug is discontinued. It is necessary to consider the possibility of drug cancellation in patients with symptoms of pancreatitis.

    In clinical studies, there was an increase in overall mortality compared to the reference drugs. The reasons for the increase in mortality are not clear. This is recommended to consider when choosing antibiotic therapy.

    Effect on the ability to drive transp. cf. and fur:
    Studies of the effect of tigecycline on the ability to manage transport and work with mechanisms have not been conducted. Patients receiving tigecycline, may experience dizziness, which may affect the ability to drive and use mechanisms.

    Form release / dosage:

    Lyophilizate for solution preparation for infusions of 50 mg.

    50 mg of tigecycline per vial of colorless glass (type I) with a capacity of 5 ml, Corked with a rubber stopper and rolled up with an aluminum cap with a plastic cap like "flip-off". 10 vials with instructions for application in a cardboard box.

    Packaging:50 mg of tigecycline per vial of colorless glass (type I) with a capacity of 5 ml, Corked with a rubber stopper and rolled up with an aluminum cap with a plastic cap like "flip-off". 10 vials with instructions for application in a cardboard box.
    Storage conditions:
    Store at a temperature not exceeding 25 ° C.
    Keep out of the reach of children.

    Shelf life:2 years. Do not use after the expiration date indicated on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-008024/09
    Date of registration:13.10.2009
    The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA
    Manufacturer: & nbsp
    Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation
    Information update date: & nbsp29.08.2015
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