Tigacil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TYGACIL (Tygacil®)

Composition:

Active substance: tigecycline;

1 vial contains 50 mg of tigecycline;

Excipients: lactose monohydrate; hydrochloric acid diluted; sodium hydroxide.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: lyophilisate in the form of a sticky mass or powder of orange color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use, tetracyclines.
ATC code J01AA12.

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 ribosome A site. This prevents the addition of amino acid residues to elongating 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 capable of overcoming two primary tetracycline resistance mechanisms: ribosomal protection and active efflux. Among Enterobacterales, there is cross-resistance between tigecycline and minocycline-resistant isolates, mediated by multidrug efflux pumps. There is no target-based cross-resistance between tigecycline and most other antibiotic classes. Tigecycline is susceptible to chromosomally encoded multidrug efflux pumps in Proteeae and Pseudomonas aeruginosa. Organisms within the Proteeae family (Proteus spp., Providencia spp., and Morganella spp.) are generally less susceptible to tigecycline than other Enterobacterales. Reduced susceptibility in both groups is associated with overexpression of the nonspecific efflux pump AcrAB, which mediates multidrug resistance. Decreased susceptibility in Acinetobacter baumannii is linked to overexpression of the AdeABC efflux pump.

Antibacterial activity in combination with other antibacterial agents

In in vitro studies, antagonism between tigecycline and other commonly used antibiotic classes was rarely observed.

Breakpoints.

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

(†) For other Enterobacterales, tigecycline activity varied from negligible for Proteus spp., Morganella morganii, and Providencia to significant for other species.

Clinical efficacy against anaerobic bacteria in polymicrobial intra-abdominal infections has been established; 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.

There is limited clinical efficacy data for tigecycline against enterococci. However, 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 drug becomes questionable, at least for certain 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*

• Anaerobes:

Clostridium perfringens†

Peptostreptococcus spp.†

Prevotella spp.

Species for which acquired resistance may be a concern

• Gram-negative aerobes:

Acinetobacter baumannii

Burkholderia cepacia

Enterobacter cloacae*

Klebsiella aerogenes

Klebsiella oxytoca*

Klebsiella pneumoniae*

Stenotrophomonas maltophilia

• Anaerobes:

Bacteroides fragilis group†

Inherently resistant species.

• Gram-negative aerobes:

Morganella morganii

Proteus spp.

Providencia spp.

Serratia marcescens

Pseudomonas aeruginosa

* Species for which satisfactory activity was demonstrated during clinical studies.

† See "Susceptibility 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 tigecycline 50 mg or 200 mg.

Pediatrics.

Tigecycline (0.75, 1, or 1.25 mg/kg) was administered in an open-label, multiple ascending dose study involving 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 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.

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 protein binding of tigecycline to plasma proteins was approximately 71–89% at concentrations observed in clinical studies (from 0.1 to 1.0 µg/mL). Pharmacokinetic studies in animals and humans have demonstrated that tigecycline rapidly distributes into tissues.

After administration of a single dose or multiple doses of 14C-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 volume of distribution of tigecycline at steady state averages 500–700 L (7–9 L/kg), indicating extensive distribution of tigecycline beyond plasma and accumulation in tissues.

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

In clinical pharmacology studies using therapeutic dosing (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 is 2349 ± 850 ng·hour/mL.

Biological transformation.

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

In vitro studies using human liver microsomes show that tigecycline does not inhibit metabolism mediated by any of the six cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 via competitive inhibition. Furthermore, tigecycline does not exhibit nicotinamide-adenine-dinucleotide-phosphate-dependent inhibition of CYP2C9, CYP2C19, CYP2D6, and CYP3A, suggesting absence of suicide 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 main route of elimination of tigecycline is biliary excretion of unchanged tigecycline. Secondary pathways include glucuronide formation and unchanged renal excretion. Total clearance of tigecycline after intravenous administration is 24 L/hour, and renal clearance is approximately 13% of total clearance. Tigecycline exhibits multi-exponential elimination from plasma; with multiple dosing, the mean elimination half-life is 42 hours, although there is considerable inter-individual variability.

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

Based on in vitro studies using a cell line characterized by overexpression of 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 or 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 was prolonged by 23% and 43%, respectively (see section "Posology and method of administration").

Renal impairment.

The pharmacokinetic profile of a single dose of tigecycline was 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 studied in two trials. The first trial included children aged 8–16 years (n=24) who received a single 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) intravenously over 30 minutes. The second trial was conducted in children aged 8–11 years who received multiple 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 intravenously over 30 minutes. Loading doses were not used in these trials. Pharmacokinetic parameters are presented in Table 2.

Table 2.

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

* 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•hour/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 result in 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 between males and females were observed. However, AUC in females was found to be 20% higher than in males.

Race.

Tigecycline clearance is not affected by race.

Body weight.

Clearance, clearance normalized to body weight, and AUC in patients with different body weights, including patients with body weight ≥ 125 kg, were not substantially different. In patients with body weight ≥ 125 kg, AUC values were 24% lower. Data for patients with body weight of 140 kg or greater are not available.

Clinical characteristics.

Indications.

Tygacil is indicated in adults and children aged 8 years and older for the treatment of (see section "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.

Tygacil should be used only when other antibiotics are not suitable for use (see section "Special precautions for use", "Adverse reactions" and "Pharmacodynamics").

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

Contraindications.

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

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

Interaction with other medicinal products and other forms of interaction.

Interaction studies were 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 carefully monitored when tigecycline is administered concomitantly with anticoagulants (see section "Special precautions for use"). Warfarin did not affect the pharmacokinetic profile of tigecycline.

Tigecycline is not extensively metabolized. Therefore, it is expected that active substances which are inhibitors or inducers of CYP450 isoenzymes will not affect its clearance. In vitro, tigecycline does not exhibit properties of a competitive inhibitor or irreversible inhibitor of CYP450 enzymes (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.

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. Combined use 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.

During clinical trials involving patients with complicated skin and soft tissue infections, complicated intra-abdominal infections, infected diabetic foot, hospital-acquired pneumonia, and trials involving patients with resistant pathogens, a higher mortality rate was observed in patients treated with tigecycline compared to patients 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.

During 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 the development of superinfection (see section "Adverse reactions").

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 another site of infection develops after initiation of tigecycline treatment, other than complicated skin and soft tissue infections or complicated intra-abdominal infections, consideration should be given to switching to an alternative antibacterial therapy with demonstrated efficacy against the specific type of infection(s) present.

Anaphylaxis.

Anaphylactic/anaphylactoid reactions, potentially life-threatening, have been reported during tigecycline use (see section "Contraindications" and "Adverse reactions").

Hepatic impairment.

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

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 tigecycline use. Adverse reactions may include photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic effects leading to increased blood urea nitrogen, azotemia, acidosis, and hyperphosphatemia (see section "Adverse reactions").

Pancreatitis.

Acute pancreatitis, which may be severe, has occurred (frequency unknown) in association with tigecycline use (see section "Adverse reactions"). The diagnosis of acute pancreatitis should be considered in patients receiving tigecycline who develop clinical symptoms, signs, or laboratory abnormalities characteristic of acute pancreatitis. Most known cases of pancreatitis occurred at least one week after initiation of tigecycline therapy. In some cases, pancreatitis occurred in patients without known risk factors for pancreatitis. Clinical improvement usually occurred 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). In addition, hypofibrinogenemia has been reported during tigecycline treatment. Therefore, coagulation parameters such as PT or other appropriate anticoagulation test, including blood fibrinogen levels, should be monitored before initiation of tigecycline therapy and regularly during treatment. Particular caution is recommended in patients with severe underlying diseases and in patients also receiving anticoagulants.

Underlying diseases.

Experience with tigecycline use for treatment of infections in patients with severe underlying diseases is limited.

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

Clinical trials of tigecycline for treatment of complicated intra-abdominal infections were predominantly conducted in 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%), perforated gastric or duodenal ulcer (8.3%), peritonitis (6.2%), and complicated diverticulitis (6.0%). Peritonitis was confirmed surgically in 77.8% of these patients. A limited number of patients with severe underlying conditions were included in the trials: immunosuppression, 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 tigecycline is used in patients with severe complicated intra-abdominal infections resulting from intestinal perforation, initial sepsis, or septic shock, consideration should be given to using combination antibacterial therapy (see section "Adverse reactions").

The effect of cholestasis on tigecycline pharmacokinetics has not been fully established. Biliary excretion accounts for approximately 50% of total elimination from the body. Therefore, patients with cholestasis should be closely monitored.

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 who develop diarrhea during or after antibacterial therapy (see section "Adverse reactions").

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

Animal studies in rats showed changes in bone pigmentation. Use of tigecycline during tooth development may lead to permanent tooth discoloration in humans (see section "Adverse reactions").

Children.

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

Adverse reactions such as nausea and vomiting are very common in children and adolescents (see section "Adverse reactions"). Dehydration should be considered as a potential consequence. Administration by intravenous infusion lasting more than 60 minutes is preferred in children.

As in adults, abdominal pain occurred frequently in children. This 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.

Tygacil should not be used in 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 "Adverse reactions").

Information on excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy. Data on tigecycline use in pregnant women are limited or nonexistent. 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 delay ossification processes in the fetus when exposure occurs in utero 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"). Tigecycline should not be used during pregnancy except in clinical situations where the woman requires tigecycline therapy.

Lactation. It is unknown whether tigecycline/metabolites are excreted in human breast milk. Available animal data show that tigecycline/metabolites are excreted in milk. Risk to newborns/infants in humans cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue/abruptly interrupt 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 did 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.

Effect on ability to drive and use machines.

Dizziness may occur during tigecycline use, which may affect the ability to drive or operate machinery (see section "Adverse reactions").

Method of Administration and Dosage.

Dosing.

Adults.

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

Children and adolescents (aged 8 to 18 years).

• 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.

The duration of treatment should be determined based on the severity of the infection, the site of infection, and the patient's clinical response.

Elderly patients.

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

Hepatic impairment.

No dosage adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

For patients (including children) with severe hepatic impairment (Child-Pugh class C), the tigecycline dose should be reduced by 50%. The recommended dose for adults is 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.

No dosage adjustment is required for patients with renal impairment or for patients undergoing hemodialysis (see section "Pharmacokinetics").

Method of administration.

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

Information on 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), 5% dextrose injection (50 mg/mL), or lactated Ringer’s injection. The contents of the vial should be gently mixed by rotating the vial 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 appropriate infusion container (e.g., a glass vial).

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

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

The reconstituted solution should be yellow to orange in color; if the solution has a different color, it should be discarded. Parenteral 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 concurrently administered drugs 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);
• lactated Ringer’s injection.

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

Children.

The safety and efficacy of Tygacil in children under 8 years of age have not been established. There are no data available.

Tygacil 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.

There is no specific information on the treatment of overdose. Following a single 60-minute intravenous dose of 300 mg tigecycline in healthy volunteers, an increased incidence of nausea and vomiting was observed.

Tigecycline is not significantly removed by hemodialysis.

Adverse Reactions

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

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

Adverse reactions reported with tigecycline use, including those identified during clinical trials and post-marketing surveillance, 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 marketing authorization 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.

Frequency not known: 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), increased serum alanine aminotransferase (ALT), hyperbilirubinemia.

Uncommon: jaundice, hepatic injury, mostly cholestatic in nature.

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, 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 tetracycline-class antibiotics. Adverse reactions associated with tetracycline-class antibiotics may include increased photosensitivity, benign intracranial hypertension, pancreatitis, and anti-anabolic effects leading to increased blood urea nitrogen, azotemia, acidosis, and hyperphosphatemia (see section “Special warnings and precautions for use”).

Administration of tigecycline during tooth development may result in permanent tooth discoloration (see section “Special warnings and precautions for use”).

In phases 3 and 4 clinical trials involving patients with complicated skin and soft tissue infections and complicated intra-abdominal infections, serious adverse reactions related to infections were reported more frequently in patients receiving tigecycline (7.1%) compared to those receiving comparator agents (5.3%). A notable difference was observed in the incidence of sepsis/septic shock with tigecycline (2.2%) versus comparators (1.1%).

During the post-treatment period, elevations in AST and ALT occurred more frequently in patients treated with tigecycline compared to those treated with comparator agents, in whom such abnormalities occurred more frequently during therapy.

In phases 3 and 4 clinical trials involving patients with complicated skin and soft tissue infections and complicated intra-abdominal infections, mortality rates were 2.4% (54/2216) in patients treated with tigecycline and 1.7% (37/2206) in patients treated with active comparator agents.

Pediatric population.

Safety data from two pharmacokinetic studies (see section “Pharmacokinetics”) are very limited. No new or unexpected safety concerns with tigecycline were observed during these studies.

The safety of tigecycline was evaluated in an open-label, single-dose, escalating-dose pharmacokinetic study involving 25 children aged 8 to 16 years who had recently recovered from infections. The adverse reaction profile of tigecycline in these children was generally consistent with that observed in adults.

The safety of tigecycline was also evaluated in an open-label, multiple-dose, escalating-dose pharmacokinetic study involving 58 children aged 8 to 11 years with complicated skin and soft tissue infections (n=15), complicated intra-abdominal infections (n=24), or community-acquired pneumonia (n=19). The adverse reaction profile of tigecycline in these children was generally consistent with that in adults, except for nausea (48.3%), vomiting (46.6%), and increased serum lipase (6.9%), which were observed at higher frequencies than in adults.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

24 months.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

The reconstituted solution should be used immediately.

Incompatibilities.

The following active substances must not be administered simultaneously with tigecycline through the same Y-site catheter: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole, omeprazole, and intravenous solutions that may increase pH above 7.

This medicinal product must not be mixed with other medicinal products unless compatibility with tigecycline has been established.

Packaging.

Powder in glass vials; 10 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Wyeth Lederle S.r.l.

Manufacturer’s name and address of place of business.

Via Franco Gorgone Z.I. - 95100 Catania (CT), Italy.