Taigobak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAYGOBAC (TAYGOBAC)

Composition:

Active substance: tigecycline;

1 vial contains 50 mg of tigecycline;

Excipients: L-arginine, nitrogen, hydrochloric acid concentrated (1 M), sodium hydroxide (1 M).

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: lyophilized mass or powder ranging from orange to orange-red in color.

Pharmacotherapeutic group.
Antibacterial agents for systemic use. Tetracyclines. ATC code J01A A12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Tigecycline, a glycylcycline-class antibiotic, inhibits bacterial protein translation by binding to the 30S ribosomal subunit and blocking the entry of aminoacyl-tRNA molecules into the ribosomal A site. This prevents the addition of amino acid residues to the growing peptide chains.

Tigecycline is generally considered to have a bacteriostatic effect. In studies evaluating the effect of tigecycline on Enterococcus spp., Staphylococcus aureus, and Escherichia coli at a concentration four times higher than the minimum inhibitory concentration (MIC), a 2 log reduction in colony count was observed.

Mechanism of resistance.

Tigecycline is able to overcome two major mechanisms of tetracycline resistance: ribosomal protection and active efflux. Among Enterobacteriaceae, cross-resistance between tigecycline and minocycline-resistant isolates exists due to efflux pumps that confer multidrug resistance. There is no cross-resistance between tigecycline and most other antibiotic classes based on the shared target site. Tigecycline is susceptible to chromosomally encoded multidrug efflux pumps in Proteae and Pseudomonas aeruginosa. Organisms within the family Proteeae (Proteus spp., Providencia spp., and Morganella spp.) are generally less susceptible to tigecycline than other members of Enterobacteriaceae. Reduced susceptibility in both groups is associated with overexpression of the nonspecific efflux pump AcrAB, which mediates multidrug resistance. Reduced susceptibility of Acinetobacter baumannii is associated with overexpression of the AdeABC efflux pump.

Breakpoints.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established the following MIC breakpoints:

• for Staphylococcus spp. — S ≤ 0.5 mg/L and R > 0.5 mg/L;
• for Streptococcus spp. species, except S. pneumoniae — S ≤ 0.25 mg/L, R > 0.5 mg/L;
• for Enterobacter spp. — S ≤ 0.25 mg/L, R > 0.5 mg/L;
• for members of Enterobacteriaceae — S ≤ 1(^) mg/L, R > 2 mg/L.

(^) In vitro activity of tigecycline is reduced against Proteus, Providencia, and Morganella spp.

Clinical efficacy against anaerobic bacteria in polymicrobial intra-abdominal infections has been demonstrated; however, there is no correlation between MIC values, pharmacokinetic/pharmacodynamic data, and clinical outcomes. Therefore, susceptibility breakpoint information is not provided. It should be noted that there is a wide range of MICs for Bacteroides and Clostridium species, which may include values exceeding 2 mg/L of tigecycline.

Clinical efficacy data for tigecycline against enterococci are limited. Nevertheless, clinical studies have demonstrated that polymicrobial intra-abdominal infections respond to treatment with tigecycline.

Susceptibility.

The frequency of acquired resistance may vary depending on the geographical location and time period of microbial sampling; local resistance data should therefore be consulted, especially when treating severe infections. When necessary, if local acquired resistance has reached a level at which the benefit of using the medicinal product becomes questionable for at least some types of infections, expert advice should be sought.

Pathogenic microorganisms

Predominantly susceptible species

Gram-positive aerobes

Enterococcus spp. † Staphylococcus aureus * Staphylococcus epidermidis Staphylococcus haemolyticus Streptococcus agalactiae* Streptococcus anginosus group* (includes S. anginosus, S. intermedius, S. constellatus) Streptococcus pyogenes* Viridans group streptococci

Gram-negative aerobes

Citrobacter freundii* Citrobacter koseri Escherichia coli* Klebsiella oxytoca*

Anaerobes

Clostridium perfringens† Peptostreptococcus spp.† Prevotella spp.

Species that may have acquired resistance

Gram-negative aerobes

Acinetobacter baumannii Burkholderia cepacia Enterobacter aerogenes

Enterobacter cloacae* Klebsiella pneumoniae* Morganella morganii Proteus spp. Providencia spp. Serratia marcescens Stenotrophomonas maltophilia

Anaerobes

Bacteroides fragilis group †

Naturally resistant species

Gram-negative aerobes

Pseudomonas aeruginosa

* Species in which adequate activity has been demonstrated in clinical studies.

† See "Breakpoints" above.

Cardiac electrophysiology.

In a randomized, placebo- and active-controlled, four-period crossover QTc interval study involving 46 healthy volunteers, no significant effect on the QTc interval was observed following a single intravenous dose of 50 mg or 200 mg of tigecycline.

Paediatric population.

Tigecycline (0.75, 1, or 1.25 mg/kg) was administered in an open-label, multiple ascending dose study to 39 children aged 8 to 11 years with complicated intra-abdominal infections or complicated skin and soft tissue infections. All patients received intravenous tigecycline for a minimum of 3 to a maximum of 14 consecutive days, with the additional option to switch to oral antibiotics on day 4 or later.

Clinical response was assessed between 10 and 21 days after the last dose. Summary results for clinical response in the modified intent-to-treat population (mITT) are presented in Table 1.

Table 1.

Clinical response, mITT population.

Indications.	0.75 mg/kg, n/N (%)	1 mg/kg, n/N (%)	1.25 mg/kg, n/N (%)
Complicated intra-abdominal infections	6/6 (100.0)	3/6 (50.0)	10/12 (83.3)
Complicated skin and soft tissue infections	3/4 (75.0)	5/7 (71.4)	2/4 (50.0)
Total	9/10 (90.0)	8/13 (62.0)	12/16 (75.0)

The efficacy data described above should be interpreted with caution, as concomitant use of antibiotics was permitted in this study; in addition, the small number of patients should be taken into account.

Pharmacokinetics.

Absorption.

Tigecycline has 100% bioavailability, as it is administered intravenously.

Distribution.

In vitro, tigecycline binding to plasma proteins is approximately 71–89% at concentrations observed in clinical studies (from 0.1 to 1.0 mcg/mL). Pharmacokinetic studies in animals and humans have demonstrated that tigecycline rapidly distributes into tissues.

Following single or multiple doses of 14C-labeled tigecycline in rats, radioactivity was widely distributed in most tissues; the highest concentrations were found in bone marrow, salivary glands, thyroid gland, spleen, and kidneys. In humans, the steady-state volume of distribution of tigecycline averages 500–700 L (7–9 L/kg), indicating extensive distribution of tigecycline beyond plasma and accumulation in tissues.

There are no data on the ability of tigecycline to cross the blood-brain barrier in humans.

In clinical pharmacology studies using a therapeutic dose (100 mg, followed by 50 mg every 12 hours), the steady-state Cmax of tigecycline in plasma was 866 ± 233 ng/mL with a 30-minute infusion and 634 ± 97 ng/mL with a 60-minute infusion. The steady-state AUC0–12h value was 2349 ± 850 ng×h/mL.

Biotransformation.

It is estimated that less than 20% of tigecycline is metabolized prior to elimination. After administration of 14C-labeled tigecycline to healthy male volunteers, unchanged 14C-labeled material was detected in urine and feces; glucuronide, N-acetyl metabolite, and epimer of tigecycline were also present.

In vitro studies using human liver microsomes show that tigecycline does not inhibit the metabolism mediated by any of the six cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 via competitive inhibition. Additionally, tigecycline shows no nicotinamide-adenine-dinucleotide-phosphate-dependent inhibition of CYP2C9, CYP2C19, CYP2D6, and CYP3A, suggesting absence of mechanism-based (suicidal) inhibition of these CYP enzymes.

Elimination.

Measurement of total radioactivity in feces and urine after administration of 14C-tigecycline shows that 59% of the dose is excreted in feces and bile, and 33% in urine. Overall, the primary route of tigecycline elimination is biliary excretion of unchanged drug. Secondary pathways include glucuronide formation and unchanged renal excretion. Total clearance of tigecycline after intravenous administration is 24 L/h, and renal clearance is approximately 13% of total clearance. Tigecycline exhibits multi-exponential elimination from plasma; after multiple dosing, the mean elimination half-life is 42 hours, although considerable inter-individual variability exists.

In vitro studies using Caco-2 cells demonstrate that tigecycline does not inhibit digoxin efflux, indicating that tigecycline is not an inhibitor of P-glycoprotein. These in vitro findings are consistent with in vivo data showing no effect of tigecycline on digoxin clearance, as observed in the drug interaction study described below (see section "Interaction with other medicinal products and other forms of interaction").

Based on in vitro studies using a cell line overexpressing P-glycoprotein, tigecycline is a substrate of P-glycoprotein. The potential contribution of P-glycoprotein-mediated transport to the in vivo distribution of tigecycline is unknown. Concomitant administration of P-glycoprotein inhibitors (e.g., ketoconazole, cyclosporine) or P-glycoprotein inducers (e.g., rifampicin) may affect the pharmacokinetics of tigecycline.

Special patient groups.

Hepatic impairment.

The pharmacokinetic profile of a single dose of tigecycline was not altered in patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (Child-Pugh classes B and C, respectively), systemic clearance of tigecycline decreased by 25% and 55%, respectively, and the elimination half-life of tigecycline increased by 23% and 43%, respectively (see section "Posology and method of administration").

Renal impairment.

The pharmacokinetic profile of a single dose of tigecycline is not altered in patients with renal impairment (creatinine clearance < 30 mL/min, n=6). In patients with severe renal impairment, AUC values were 30% higher than in patients with normal renal function (see section "Posology and method of administration").

Elderly patients.

Overall, no differences in pharmacokinetic parameters were observed between healthy elderly and younger volunteers (see section "Posology and method of administration").

Paediatric population.

The pharmacokinetics of tigecycline were evaluated in two studies. The first study included children aged 8–16 years (n=24) who received a single intravenous dose of tigecycline (0.5 mg/kg, 1 mg/kg, or 2 mg/kg, up to a maximum dose of 50 mg, 100 mg, and 150 mg, respectively) infused over 30 minutes. The second study was conducted in children aged 8–11 years (n=42) who received multiple intravenous doses of tigecycline (0.75 mg/kg, 1 mg/kg, or 1.25 mg/kg, up to a maximum dose of 50 mg) every 12 hours, infused over 30 minutes. Loading doses were not used in these studies. Pharmacokinetic parameters are presented in Table 2.

Table 2.

Dose normalized to 1 mg/kg, mean ± standard deviation of Cmax and AUC of tigecycline in children.

Age (years)	N	Cmax (ng/mL)	AUC (ng×h/mL)*
Single dose
8–11	8	3881 ± 6637	4034 ± 2874
12–16	16	8508 ± 11,433	7026 ± 4088
Multiple doses
8–11	42	1911 ± 3032	2404 ± 1000

* Single dose — AUC0–∞; multiple dose — AUC0–12h.

The target AUC0–12h in adults following administration of the recommended loading dose of 100 mg and a maintenance dose of 50 mg every 12 hours was approximately 2500 ng×h/mL. Population pharmacokinetic analysis from both studies identified body weight as a covariate of tigecycline clearance in children aged 8 years and older. A dosing regimen of 1.2 mg/kg tigecycline every 12 hours (up to a maximum dose of 50 mg every 12 hours) for children aged 8–12 years and 50 mg every 12 hours for adolescents aged 12–18 years is expected to achieve drug exposure similar to that observed in adults receiving the approved dosing regimen.

During these studies, higher Cmax values were observed in some pediatric patients compared to adults. Therefore, the infusion rate of tigecycline in pediatric patients should be selected with caution.

Sex

No clinically significant differences in tigecycline clearance were observed between males and females. However, AUC in females was found to be 20% higher than in males.

Race

Tigecycline clearance is not influenced by race.

Body weight

Clearance, clearance normalized by body weight, and AUC in patients with different body weights, including patients weighing ≥ 125 kg, were not significantly different. In patients weighing ≥ 125 kg, AUC values were 24% lower. There are no data available for patients with body weight of 140 kg or greater.

Clinical characteristics.

Indications.

The medicinal product is indicated in adults and children aged 8 years and older for the treatment of (see sections "Special precautions for use" and "Pharmacodynamics"):

• complicated skin and soft tissue infections, excluding infected diabetic foot (see section "Special precautions for use");
• complicated intra-abdominal infections.

The medicinal product should be used only when other antibiotics are unsuitable for use (see sections "Special precautions for use", "Adverse reactions", and "Pharmacodynamics").

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in section "Composition".

Patients with hypersensitivity to tetracycline-class antibiotics may exhibit hypersensitivity to tigecycline.

Interaction with other medicinal products and other forms of interactions.

Interaction studies have been conducted only in adults.

Concomitant administration of tigecycline and warfarin (25 mg single dose) to healthy volunteers resulted in a 40% and 23% reduction in the clearance of R-warfarin and S-warfarin, respectively, and an increase in AUC by 68% and 29%, respectively. The mechanism of this interaction is not yet known. Based on available data, it cannot be assumed that this interaction may lead to significant changes in the international normalized ratio (INR). However, since tigecycline may prolong both prothrombin time and activated partial thromboplastin time, coagulation parameters should be closely monitored when tigecycline is used concomitantly with anticoagulants (see section "Special precautions for use"). Warfarin did not affect the pharmacokinetic profile of tigecycline.

Tigecycline is not extensively metabolized. Therefore, active substances that are inhibitors or inducers of CYP450 isoenzymes are not expected to affect its clearance. Tigecycline does not exhibit properties of a competitive inhibitor or irreversible inhibitor of CYP450 enzymes in vitro (see section "Pharmacokinetics"). Tigecycline at recommended doses does not affect the rate or extent of absorption or clearance of digoxin (0.5 mg, followed by 0.25 mg daily) when administered to healthy adult volunteers. Digoxin does not affect the pharmacokinetic profile of tigecycline. Therefore, no dose adjustment is required when tigecycline is used concomitantly with digoxin.

In vitro studies have shown no antagonism between tigecycline and antibiotics from other classes commonly used in therapy.

Concomitant use of antibiotics with oral contraceptives may reduce the efficacy of contraceptives.

Concomitant administration of tigecycline and calcineurin inhibitors, such as tacrolimus or cyclosporine, may lead to increased minimum serum concentrations of calcineurin inhibitors. Therefore, serum concentrations of calcineurin inhibitors should be monitored during tigecycline treatment to avoid drug toxicity.

According to in vitro study results, tigecycline is a substrate of P-glycoprotein. Coadministration with P-glycoprotein inhibitors (e.g., ketoconazole or cyclosporine) or P-glycoprotein inducers (e.g., rifampicin) may affect the pharmacokinetics of tigecycline (see section "Pharmacokinetics").

Special precautions for use.

In clinical trials involving patients with complicated skin and soft tissue infections, complicated intra-abdominal infections, infected diabetic foot, hospital-acquired pneumonia, and studies involving patients with resistant pathogens, a higher mortality rate was observed in patients treated with tigecycline compared to those treated with comparator agents. The reasons for this remain unknown, but cannot exclude lower efficacy and safety compared to the comparator agents used in the trials. Superinfection.

In clinical trials in patients with complicated intra-abdominal infections, impaired surgical wound healing was associated with superinfection. Patients with impaired healing should be closely monitored for signs of superinfection (see section "Side effects").

Patients who develop superinfections, including hospital-acquired pneumonia, are likely to have poorer treatment outcomes. Patients should be carefully monitored for the development of superinfection. If, after initiation of tigecycline, another site of infection develops, other than complicated skin and soft tissue infections or complicated intra-abdominal infections, consideration should be given to switching to an alternative antibacterial therapy proven effective against the specific type(s) of infection present.

Anaphylaxis.

Anaphylactic/anaphylactoid reactions, potentially life-threatening, have been reported during treatment with tigecycline (see section "Contraindications" and "Side effects").

Hepatic impairment.

Cases of liver injury, predominantly of cholestatic type, including cases of hepatic failure with fatal outcome, have been reported in patients receiving tigecycline. Although the development of hepatic failure in patients treated with tigecycline may be attributable to underlying diseases or concomitant medications, a potential contribution of tigecycline to the development of this condition should be considered (see section "Side effects").

Tetracycline-class antibiotics.

Glycylcycline antibiotics are structurally similar to tetracycline-class antibiotics. Adverse reactions similar to those observed with tetracycline-class antibiotics may occur during treatment with tigecycline. Such adverse reactions may include photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic effects leading to increased blood urea nitrogen, azotemia, acidosis, and hyperphosphatemia (see section "Side effects").

Pancreatitis.

Acute pancreatitis, which may be severe, has occurred (frequency unknown) in association with tigecycline use (see section "Side effects"). The diagnosis of acute pancreatitis should be considered in patients receiving tigecycline who develop clinical symptoms, signs, or laboratory abnormalities typical of acute pancreatitis. Most known cases of pancreatitis occurred at least one week after initiation of tigecycline therapy. In some cases, pancreatitis developed in patients without known risk factors for pancreatitis. Improvement in patients' condition is usually observed after discontinuation of tigecycline. Consideration should be given to discontinuing tigecycline if pancreatitis is suspected.

Coagulopathy.

Tigecycline may prolong both prothrombin time (PT) and activated partial thromboplastin time (aPTT). Additionally, hypofibrinogenemia has been reported during tigecycline treatment. Therefore, coagulation parameters such as PT or another appropriate anticoagulation test parameter, including blood fibrinogen levels, should be monitored before initiating tigecycline treatment and regularly during therapy. Particular caution is recommended in patients with severe underlying diseases and in those receiving concomitant anticoagulant therapy.

Underlying diseases.

Experience with tigecycline use in infections among patients with serious underlying conditions is limited.

Clinical trials evaluating tigecycline for the treatment of complicated skin and soft tissue infections primarily included patients with cellulitis (58.6%) and subsequent severe abscesses (24.9%). Patients with significant underlying conditions such as immunocompromised status, infected pressure ulcers, or those requiring treatment longer than 14 days (e.g., necrotizing fasciitis) were excluded from these trials. A limited number of patients with comorbidities such as diabetes mellitus (25.8%), peripheral vascular disease (10.4%), intravenous drug use (4.0%), or HIV infection (1.2%) were included. Limited experience also exists in treating patients with concomitant bacteremia (3.4%). Therefore, caution is required when treating such patients. Results from a large study in patients with infected diabetic foot showed lower efficacy of tigecycline compared to the reference agent; therefore, its use is not recommended in this patient group (see section "Indications").

Clinical trials evaluating tigecycline for the treatment of complicated intra-abdominal infections primarily included patients with complicated appendicitis (50.3%), as well as patients with less common diagnoses such as complicated cholecystitis (9.6%), intestinal perforation (9.6%), intra-abdominal abscess (8.7%), gastric or duodenal ulcer perforation (8.3%), peritonitis (6.2%), and complicated diverticulitis (6.0%). Peritonitis was surgically confirmed in 77.8% of these patients. A limited number of patients with serious underlying conditions were included in the trials: immunocompromised status, clinical severity score APACHE II > 15 (3.34%), surgically confirmed multiple intra-abdominal abscesses (11.4%). Limited experience also exists in treating patients with concomitant bacteremia (5.6%). Therefore, caution is required when treating such patients.

When treating patients with severe complicated intra-abdominal infections resulting from intestinal perforation, early sepsis, or septic shock, consideration should be given to using combination antibacterial therapy (see section "Side effects"). The impact of cholestasis on tigecycline pharmacokinetics has not been fully established. Biliary excretion of tigecycline accounts for approximately 50% of total elimination from the body. Therefore, careful monitoring of patients with cholestasis is required. Pseudomembranous colitis, ranging in severity from mild to life-threatening, has been reported with nearly all antibacterial agents. Therefore, it is important to consider this diagnosis in patients presenting with diarrhea during or following treatment with any antibacterial agent (see section "Side effects").

Tigecycline use may lead to overgrowth of non-susceptible organisms, including fungi. Patients should be closely monitored during treatment (see section "Side effects").

Studies in rats treated with tigecycline showed discoloration of bones. Use of tigecycline during tooth development may lead to permanent tooth discoloration in humans (see section "Side effects").

Children.

Clinical experience with tigecycline for treatment of infections in children aged 8 years and older is very limited (see section "Side effects" and "Pharmacodynamics"). Therefore, use of this medicinal product should be restricted to clinical situations where no alternative antibacterial therapy is available.

Adverse reactions such as nausea and vomiting are very commonly observed in children and adolescents (see section "Side effects"). The potential for dehydration should be considered. The drug should preferably be administered to children by intravenous infusion over more than 60 minutes.

As in adults, abdominal pain has been frequently observed in children. Such pain may indicate pancreatitis. If pancreatitis develops, tigecycline should be discontinued.

Liver function tests, coagulation parameters, blood counts, and levels of amylase and lipase should be monitored regularly before and during tigecycline treatment.

The medicinal product should not be administered to children under 8 years of age due to lack of safety and efficacy data in this age group and because tigecycline may be associated with permanent tooth discoloration (see section "Dosage and administration" and "Side effects").

Information on excipients.

The medicinal product contains less than 1 mmol sodium (23 mg) per 5 mL of solution. Patients on a low-sodium diet may be informed that this medicinal product is essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy.

There is no or limited information on tigecycline use in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown. Like tetracycline-class antibiotics, tigecycline may cause permanent tooth damage (discoloration and enamel defects) and impair bone ossification in the fetus following in utero exposure during the second half of pregnancy, as well as in children under 8 years of age, due to accumulation in tissues with high calcium turnover and formation of calcium-containing chelate complexes (see section "Special precautions for use"). The medicinal product should not be used during pregnancy except in clinical situations where the woman requires tigecycline treatment.

Lactation (breastfeeding).

It is unknown whether tigecycline/metabolites are excreted in human breast milk. Available pharmacodynamic/toxicological data from animal studies demonstrate that tigecycline/metabolites are excreted in milk. Risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from tigecycline therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility.

The effect of tigecycline on human fertility has not been studied. Preclinical studies in rats do not indicate harmful effects on fertility or reproductive function. In female rats, no drug-related effects on ovaries or ovarian cycles were observed at doses up to 4.7 times the human daily dose based on AUC values.

Effects on ability to drive and use machines.

Dizziness may occur during treatment with tigecycline, which may affect the ability to drive or operate machinery (see section "Side effects").

Method of Administration and Dosage

Dosage.

Adults.

The recommended initial dose for adults is 100 mg, followed by 50 mg every 12 hours for 5–14 days.

The duration of treatment depends on the severity of the infection, the site of infection, and the patient's clinical response.

Children and adolescents (aged 8 to 17 years).

Tigecycline should be used for the treatment of children aged 8 years and older only after consultation with a physician experienced in the management of infections.

• Children aged 8 to 12 years: 1.2 mg/kg of tigecycline every 12 hours administered intravenously, with a maximum dose of 50 mg every 12 hours for 5–14 days.
• Adolescents aged 12 to 18 years: 50 mg every 12 hours for 5–14 days.

Elderly patients.

Dose adjustment in elderly patients is not required (see section "Pharmacokinetics").

Hepatic impairment.

Dose adjustment is not required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

In patients (including children) with severe hepatic impairment (Child-Pugh class C), the dose of tigecycline should be reduced by 50%. The adult dose should be reduced to 25 mg every 12 hours after an initial loading dose of 100 mg. The drug should be used with caution and treatment response should be closely monitored in patients with severe hepatic impairment (Child-Pugh class C) (see sections "Special precautions" and "Pharmacokinetics").

Renal impairment.

Dose adjustment is not required in patients with renal impairment or in patients undergoing hemodialysis (see section "Pharmacokinetics").

Method of Administration.

Tigecycline must be administered only by intravenous infusion over 30 to 60 minutes (see section "Special precautions"). In children, tigecycline should preferably be administered by intravenous infusion lasting more than 60 minutes (see section "Special precautions").

Reconstitution and Dilution of the Medicinal Product Prior to Administration.

To achieve a tigecycline concentration of 10 mg/mL, the powder should be reconstituted with 5.3 mL of 0.9% sodium chloride injection (9 mg/mL) or 5% dextrose injection (50 mg/mL).

The contents of the vial should be gently mixed by swirling until the powder is completely dissolved. Then, 5 mL of the resulting solution should be immediately withdrawn from the vial and added to an intravenous infusion bag containing 100 mL or another suitable infusion container (e.g., a glass vial or I.V. bag).

To obtain a 100 mg dose, the contents of two vials should be reconstituted and added to a 100 mL intravenous infusion bag or another suitable infusion container (e.g., a glass vial or I.V. bag).

Note: Each vial contains a 6% overage; therefore, 5 mL of the reconstituted solution is equivalent to 50 mg of the active substance.

The reconstituted solution should be yellow to orange in color; if the solution has a different color, it should be discarded. Parenteral medicinal products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration.

Tigecycline should be administered intravenously through a dedicated intravenous line or via a Y-site catheter. If the same line is used for sequential administration of multiple drugs, it should be flushed before and after tigecycline administration with 0.9% sodium chloride injection (9 mg/mL) or 5% dextrose injection (50 mg/mL). When administering through a common line, infusion solutions compatible with both tigecycline and other medicinal products administered through the same line must be used (see section "Incompatibilities").

The vial is intended for single use only; any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Compatible intravenous infusion solutions:

• 0.9% sodium chloride injection (9 mg/mL);
• 5% dextrose injection (50 mg/mL).

Compatibility via Y-site catheter has been confirmed for tigecycline solution prepared with 0.9% sodium chloride injection and the following medicinal products or diluents: amikacin, dobutamine, dopamine hydrochloride, gentamicin, haloperidol, lidocaine hydrochloride, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA-containing formulation), potassium chloride, propofol, ranitidine hydrochloride, theophylline, and tobramycin.

Children.

The safety and efficacy of tigecycline in children under 8 years of age have not been established. Data are lacking.

The medicinal product should not be used in children under 8 years of age due to the risk of tooth discoloration (see sections "Special precautions" and "Pharmacodynamics").

Overdose.

Symptoms. Following a single 300 mg intravenous dose of tigecycline administered over 60 minutes to healthy volunteers, an increased incidence of nausea and vomiting was observed.

Treatment. There is no specific information on the treatment of overdose. Tigecycline is not significantly removed by hemodialysis.

Adverse Reactions

Overall, during phases 3 and 4 of clinical trials, tigecycline was administered to 2393 patients with complicated skin and soft tissue infections and complicated intra-abdominal infections.

During clinical studies, the most commonly reported adverse reactions associated with the use of the medicinal product were nausea (21%) and vomiting (13%). These reactions were mostly mild or moderate in severity, usually occurred early in treatment (within 1–2 days), and were reversible.

Adverse reactions reported during tigecycline use, including those identified during clinical and post-marketing studies, are listed below by frequency: very common — ≥ 1/10; common — ≥ 1/100 and < 1/10; uncommon — ≥ 1/1000 and < 1/100; rare — ≥ 1/10000 and < 1/1000; very rare — < 1/10000; frequency not known (cannot be estimated based on available data).

Adverse reactions identified after tigecycline was marketed are marked with an asterisk «*».

Infections and infestations.

Common: sepsis/septic shock, pneumonia, abscess, infections.

Blood and lymphatic system disorders.

Common: prolonged activated partial thromboplastin time, prolonged prothrombin time.

Uncommon: thrombocytopenia, increased international normalized ratio (INR).

Rare: hypofibrinogenemia.

Immune system disorders.

Frequency not known: anaphylactic/anaphylactoid reactions* (see section «Contraindications» and «Special warnings and precautions for use»).

Metabolism and nutrition disorders.

Common: hypoglycemia, hypoproteinemia.

Nervous system disorders.

Common: dizziness.

Vascular disorders.

Common: phlebitis.

Uncommon: thrombophlebitis.

Gastrointestinal disorders.

Very common: nausea, vomiting, diarrhea.

Common: abdominal pain, dyspepsia, anorexia.

Uncommon: acute pancreatitis (see section «Special warnings and precautions for use»).

Hepatobiliary disorders.

Common: increased serum aspartate aminotransferase (AST) levels, increased serum alanine aminotransferase (ALT) levels, hyperbilirubinemia.

Uncommon: jaundice, hepatic injury, mostly cholestatic.

Frequency not known: liver failure* (see section «Special warnings and precautions for use»).

Skin and subcutaneous tissue disorders.

Common: pruritus, rash.

Frequency not known: severe skin reactions, including Stevens-Johnson syndrome*.

General disorders and administration site conditions.

Common: impaired healing, injection site reactions, headache.

Uncommon: injection site inflammation, injection site pain, injection site swelling, injection site phlebitis.

Investigations.

Common: increased serum amylase levels, increased blood urea nitrogen (BUN).

Adverse reactions associated with antibiotics.

• Pseudomembranous colitis, ranging from mild to life-threatening (see section «Special warnings and precautions for use»).
• Overgrowth of antibiotic-resistant microorganisms, including fungi (see section «Special warnings and precautions for use»).

Adverse reactions associated with tetracycline-class antibiotics.

Glycylcycline antibiotics are structurally similar to tetr游戏副本