Tygacil-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIGECYCLINE-VISTA (TIGECYCLINE-VISTA)

Composition:

active substance: tigecycline;

1 vial contains 50 mg of tigecycline;

excipients: maltose monohydrate; hydrochloric acid, diluted; sodium hydroxide; water for injections.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physico-chemical properties: lyophilized orange-colored powder.

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 incorporation of amino acid residues into 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 major mechanisms of tetracycline resistance: ribosomal protection and active efflux. Among Enterobacteriaceae, cross-resistance exists between tigecycline and minocycline-resistant isolates, mediated by efflux pumps that confer multidrug resistance. There is no clinically significant cross-resistance between tigecycline and most other classes of antibiotics based on the target site of action. However, tigecycline is susceptible to chromosomally encoded multidrug efflux pumps in Proteеае and Pseudomonas aeruginosa. Organisms within the Proteeae family (Proteus spp., Providencia spp., and Morganella spp.) are generally less susceptible to tigecycline compared to other Enterobacteriaceae. Reduced susceptibility in both groups is associated with overexpression of the nonspecific multidrug efflux pump AcrAB. 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 classes of antibiotics was rarely observed.

Breakpoints

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

EUCAST breakpoints
Pathogen	Minimum inhibitory concentration (MIC) breakpoint (mg/l)
	≤ S (Susceptible)	> R (Resistant)
Enterobacterales: Escherichia coli and Citrobacter koseri: (†)	≤ 0.5	> 0.5
Staphylococcus spp.	≤ 0.5	> 0.5
Enterococcus spp.	≤ 0.25	> 0.25
Streptococcus groups A, B, C and G	≤ 0.125	> 0.125

(†) For other Enterobacterales, tigecycline activity varied from negligible for Proteus spp., Morganella morganii, and Providencia to substantial 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 data are not provided. It should be noted that a wide range of MICs has been observed 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 the time period during which microorganisms are collected; local resistance data are therefore desirable, especially when treating severe infections. If necessary, when local acquired resistance reaches a level at which the benefit of using the medicinal product 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 problem

• Gram-negative aerobes:

Acinetobacter baumannii, Burkholderia cepacia, Enterobacter cloacae*, Klebsiella aerogenes, Klebsiella oxytoca*, Klebsiella pneumoniae*, Stenotrophomonas maltophilia

• Anaerobes:

Bacteroides fragilis group†

Species inherently resistant

• Gram-negative aerobes:

Morganella morganii

Proteus spp., Providencia spp., Serratia marcescens, Pseudomonas aeruginosa

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

† 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 after administration of a single 50 mg or 200 mg intravenous dose of tigecycline.

Paediatric population

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 days and up to 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 (mITT) population 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)	3/6 (50)	10/12 (83.3)
Complicated skin and soft tissue infections	3/4 (75)	5/7 (71.4)	2/4 (50)
Total	9/10 (90)	8/13 (62)	12/16 (75)

The efficacy data presented 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 ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 µg/mL). Pharmacokinetic studies in animals and humans have demonstrated that tigecycline rapidly distributes into tissues.

After single or multiple doses of 14C-tigecycline in rats, radioactivity was widely distributed in most tissues, with the highest concentrations found in bone marrow, salivary glands, thyroid gland, spleen, and kidneys. In humans, the mean steady-state volume of distribution of tigecycline is 500–700 L (7–9 L/kg), indicating extensive distribution 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 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·hour/mL.

Metabolism

It is estimated that 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; 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 (NADPH) dependency in the inhibition of CYP2C9, CYP2C19, CYP2D6, and CYP3A, suggesting absence of mechanism-based (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% is excreted in urine. Overall, the primary route of tigecycline elimination is biliary excretion of unchanged drug. Secondary pathways include glucuronide formation and renal excretion of unchanged drug. Total clearance of tigecycline after intravenous administration is 24 L/hour, with renal clearance accounting for approximately 13% of total clearance. Tigecycline exhibits multi-exponential elimination from plasma; with 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 transport, indicating that tigecycline is not a P-glycoprotein inhibitor. These in vitro findings are consistent with the lack of effect of tigecycline on digoxin clearance observed in the in vivo 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 or cyclosporine) or P-glycoprotein inducers (e.g., rifampicin) may affect the pharmacokinetics of tigecycline.

Special patient populations

Hepatic impairment

The pharmacokinetic profile of a single dose of tigecycline is 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 is reduced by 25% and 55%, respectively, and the elimination half-life is prolonged 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 have been observed between elderly and younger healthy volunteers (see section "Posology and method of administration").

Paediatric population

The pharmacokinetics of tigecycline have been studied in two trials. The first trial 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 trial was conducted in children aged 8–11 years 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 trials. Pharmacokinetic parameters are presented in Table 2.

Table 2

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

Age (years)	N	Cmax (ng/mL)	AUC (ng•hour/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•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 achieve drug exposure similar to that observed in adults receiving the approved dosing regimen. During these studies, some children showed higher Cmax values compared to adults. Therefore, the infusion rate of tigecycline in pediatric patients should be selected with caution.

Gender

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

Race

Tigecycline clearance is not influenced by race.

Body weight

Clearance adjusted for body weight and AUC in patients with different body weights, including patients with body weight ≥ 125 kg, did not differ significantly. In patients with body weight ≥ 125 kg, AUC values were 24% lower. Data for patients with body weight of 140 kg and above are not available.

Clinical characteristics

Indications

Tigecycline-Vistu is indicated for use in adults and children aged 8 years and older for the treatment of (see section "Special instructions" and "Pharmacodynamics"):

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

Tigecycline-Vistu should be used only when other antibiotics are unsuitable for use (see sections "Special instructions", "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 the section "Composition".

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

Interaction with other medicinal products and other forms of interaction

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 is unlikely 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 instructions"). 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. 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, dose adjustment is not required when tigecycline is used concomitantly with digoxin. In vitro studies have not revealed 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 use of tigecycline with 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

In clinical trials involving patients with complicated skin and soft tissue infections, complicated intra-abdominal infections, infected diabetic foot, hospital-acquired pneumonia, and in trials involving patients with resistant pathogens, a higher mortality rate was observed among 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, wound healing complications were associated with superinfection in patients with complicated intra-abdominal infections. Patients with impaired wound healing should be closely monitored for signs of superinfection (see section "Adverse reactions"). Patients who develop superinfections, including hospital-acquired pneumonia, are likely to have poorer treatment outcomes. Close monitoring for the development of superinfection is required. 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 proven effective for the specific type of infection present.

Anaphylaxis

Anaphylactic/anaphylactoid reactions, which may be life-threatening, have been reported with tigecycline (see sections "Contraindications" and "Adverse reactions").

Hepatic impairment

Cases of liver injury, predominantly of cholestatic type, including cases of liver failure with fatal outcome, have been reported in patients treated with tigecycline. Although the development of liver failure in patients treated with tigecycline may be attributable to underlying diseases or concomitant medications, a potential contribution of tigecycline to this condition cannot be ruled out (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 with tigecycline. These 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"). Acute pancreatitis should be considered in patients receiving tigecycline who develop clinical symptoms, signs, or laboratory abnormalities typical of acute pancreatitis. Most reported cases of pancreatitis occurred at least one week after initiation of tigecycline. In some cases, pancreatitis occurred in patients without known risk factors for pancreatitis. Clinical improvement usually followed discontinuation of tigecycline. Discontinuation of tigecycline should be considered 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 other appropriate anticoagulation tests, including blood fibrinogen levels, should be monitored before initiating tigecycline therapy and regularly during treatment. Particular caution is recommended in patients with severe underlying diseases and in those receiving concomitant anticoagulant therapy.

Underlying diseases

Experience with tigecycline use in patients with severe underlying diseases is limited. Clinical trials of tigecycline for treatment of complicated skin and soft tissue infections primarily included patients with cellulitis (58.6%) and deep-seated 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%), and HIV infection (1.2%) were included. Limited experience also exists in treating 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 complicated intra-abdominal infections primarily included patients with complicated appendicitis (50.3%) and 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%). Peritonitis was found 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 using tigecycline in patients with severe complicated intra-abdominal infections due to intestinal perforation, early sepsis, or septic shock, consideration should be given to combination antibacterial therapy (see section "Adverse reactions"). The impact of cholestasis on tigecycline pharmacokinetics has not been fully established. Approximately 50% of the total amount eliminated from the body is excreted via bile. Therefore, careful monitoring of patients with cholestasis is required. Patients receiving tigecycline concomitantly with anticoagulants should be monitored with prothrombin time or other appropriate coagulation tests (see section "Interaction with other medicinal products and other forms of interaction"). 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 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"). Rat studies with tigecycline showed bone discoloration. Use of tigecycline during tooth development may lead to permanent tooth discoloration in humans (see section "Adverse reactions").

Paediatric population

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 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 "Adverse reactions"). Dehydration should be considered as a potential complication. Tigecycline 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. 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.

The medicinal product should not be used in children under 8 years of age due to lack of information on safety and efficacy in this age group, and because tigecycline may be associated with permanent tooth discoloration (see sections "Dosage and administration" and "Adverse reactions").

Important information on excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

There is limited or no information on the use of tigecycline in pregnant women. Animal studies have shown reproductive toxicity. The potential risk in humans is unknown. Like tetracycline-class antibiotics, tigecycline may cause permanent tooth damage (discoloration and enamel defects) and impair bone ossification in the fetus when exposure occurs in utero during the second half of pregnancy, and 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 pharmacodynamic/toxicological data from animal studies show 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/abandon tigecycline therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Tigecycline did not affect mating or fertility in rats at doses up to 4.7 times the human daily dose based on AUC. No tigecycline-related effects on ovaries or ovarian cycles were observed in female rats at doses up to 4.7 times the human daily dose based on AUC.

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 "Adverse reactions").

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

Children and adolescents (aged 8 to 18 years)

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

• Children aged 8 to 12 years: 1.2 mg/kg 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

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

In patients (including children) with severe hepatic impairment (Child-Pugh class C), the dose of tigecycline should be reduced by 50%. The tigecycline dose for adults should be reduced to 25 mg every 12 hours following a 100 mg loading dose. 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 dose adjustment is 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").

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

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

Note: The vial contains a 6% overage; therefore, 5 mL of the prepared 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. Prior to administration, the medicinal product should be visually inspected for particulate matter and discoloration (e.g., green or black).

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 solutions for intravenous administration:

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

When administered via a Y-site catheter, compatibility of tigecycline solution prepared with 0.9% sodium chloride has been confirmed with the following medicinal products or diluents: amikacin, dobutamine, dopamine hydrochloride, gentamicin, haloperidol, lactated Ringer's solution, 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. Tigecycline-Vistu should not be used in children under 8 years of age due to tooth discoloration (see sections "Special precautions" and "Pharmacodynamics").

Overdose

Symptoms. Following a single 60-minute intravenous dose of 300 mg tigecycline in healthy volunteers, an increased incidence of nausea and vomiting was observed.

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

Adverse Reactions

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

The most commonly reported adverse reactions associated with tigecycline use 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 during tigecycline use, including those observed during clinical trials and post-marketing surveillance, are listed below according to frequency: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10,000 and < 1/1000; very rare: < 1/10,000; frequency not known (cannot be estimated from available data).

Post-marketing adverse reactions associated with tigecycline are indicated by the symbol «*».

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), increased serum alanine aminotransferase (ALT), hyperbilirubinemia.

Uncommon: jaundice, hepatic injury, mostly cholestatic.

Frequency not known: hepatic 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.

Adverse reactions typical of 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 typical of 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»).

During 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 comparator agents (1.1%).

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

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

Paediatric 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 pharmacokinetic study involving 25 children aged 8 to 16 years who had recently recovered from infections. The adverse reaction profile of tigecycline in these patients was generally consistent with that observed in adults.

The safety of tigecycline was also evaluated in an open-label, multiple-dose escalating 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 occurred more frequently than in adults.

Reporting suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or 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

2 years.

The reconstituted solution may be stored for up to 24 hours (up to 6 hours in the vial, 18 hours in the I.V. bag) at a temperature not exceeding 25 °C.

After dilution with 0.9% sodium chloride solution or 5% dextrose solution, the solution may be stored for 48 hours at 2–8 °C.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

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 the pH above 7.

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

Packaging

50 mg of powder in glass vials; 10 vials per cardboard box.

Prescription status

Prescription only.

Manufacturer

VEM ILAC San. ve Tik. A.S.

Manufacturer's address and place of business

Cerkezkoy Organize Sanayi Bolgesi, Karaagac Mahallesi, Fatih Bulvari No 38, Kapakli / Tekirdag / Turkey.