Complicated Skin and Skin Structure Infections
Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of
complicated skin and skin structure infections caused by susceptible isolates of Escherichia
coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus
(methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus
anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus
pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.

Complicated Intra-abdominal Infections
Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of
complicated intra-abdominal infections caused by susceptible isolates of Citrobacter freundii,
Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae,
Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus
(methicillinsusceptible and -resistant isolates), Streptococcus anginosus grp. (includes S.
anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides
thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and
Peptostreptococcus micros.

Community-Acquired Bacterial Pneumonia
Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of
community-acquired bacterial pneumonia caused by susceptible isolates of Streptococcus
pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia,
Haemophilus influenzae, and Legionella pneumophila.

Limitations of Use
Tigecycline for injection is not indicated for the treatment of diabetic foot infections. A
clinical trial failed to demonstrate non-inferiority of Tigecycline for injection for treatment of
diabetic foot infections.
Tigecycline for injection is not indicated for the treatment of hospital-acquired or ventilatorassociated
pneumonia. In a comparative clinical trial, greater mortality and decreased
efficacy were reported in Tigecycline for injection-treated patients [see Warnings and
Precautions (4.4)].

Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Tigecycline for injection and other antibacterial drugs, Tigecycline for injection should be
used only to treat infections that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information are available, they should be considered
in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Appropriate specimens for bacteriological examination should be obtained in order to isolate
and identify the causative organisms and to determine their susceptibility to tigecycline.
Tigecycline for injection may be initiated as empiric monotherapy before results of these tests
are known.

Recommended Adult Dosage
The recommended dosage regimen for Tigecycline For Injection is an initial dose of 100 mg,
followed by 50 mg every 12 hours. Intravenous infusions of Tigecycline For Injection should
be administered over approximately 30 to 60 minutes every 12 hours.
The recommended duration of treatment with Tigecycline For Injection for complicated skin
and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days.

The recommended duration of treatment with Tigecycline For Injection for communityacquired
bacterial pneumonia is 7 to 14 days. The duration of therapy should be guided by
the severity and site of the infection and the patient’s clinical and bacteriological progress.

Dosage in Patients with Hepatic Impairment
No dosage adjustment is warranted in patients with mild to moderate hepatic impairment
(Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh
C), the initial dose of Tigecycline For Injection should be 100 mg followed by a reduced
maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child
Pugh C) should be treated with caution and monitored for treatment response [see Clinical
Pharmacology (5.2) and Use in Specific Populations.

Dosage in Pediatric Patients
The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated
due to the observed increase in mortality associated with Tigecycline For Injection in adult
patients. Avoid use of Tigecycline For Injection in pediatric patients unless no alternative
antibacterial drugs are available. Under these circumstances, the following doses are
suggested
- Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of Tigecycline For Injection
every 12 hours intravenously to a maximum dose of 50 mg of Tigecycline For Injection every
12 hours.
- Pediatric patients aged 12 to 17 years should receive 50 mg of Tigecycline For Injection
every 12 hours.
The proposed pediatric doses of Tigecycline For Injection were chosen based on exposures
observed in pharmacokinetic trials, which included small numbers of pediatric patients [see
Use in Specific Populations and Clinical Pharmacology

Preparation and Administration
Each vial of Tigecycline For Injection should be reconstituted with 5.3 mL of 0.9% Sodium
Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer’s Injection, USP to
achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage.
Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be
gently swirled until the drug dissolves. Reconstituted solution must be transferred and further
diluted for intravenous infusion. Withdraw 5 mL of the reconstituted solution from the vial
and add to a 100 mL intravenous bag for infusion (for a 100 mg dose, reconstitute two vials;
for a 50 mg dose, reconstitute one vial). The maximum concentration in the intravenous bag
should be 1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the
solution should be discarded. Parenteral drug products should be inspected visually for
particulate matter and discoloration (e.g., green or black) prior to administration. Once
reconstituted, Tigecycline For Injection may be stored at room temperature (not to exceed
25ºC/77ºF) for up to 24 hours (up to 6 hours in the vial and the remaining time in the
intravenous bag). If the storage conditions exceed 25ºC (77ºF) after reconstitution,
tigecycline should be used immediately. Alternatively, Tigecycline For Injection mixed with
0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored
refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the
reconstituted solution into the intravenous bag. Tigecycline For Injection may be
administered intravenously through a dedicated line or through a Y-site. If the same
intravenous line is used for sequential infusion of several drugs, the line should be flushed
before and after infusion of Tigecycline For Injection with 0.9% Sodium Chloride Injection,
USP, 5% Dextrose Injection, USP or Lactated Ringer’s Injection, USP. Injection should be
made with an infusion solution compatible with tigecycline and with any other drug(s)
administered via this common line.

Drug Compatibilities
Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5%
Dextrose Injection, USP, and Lactated Ringer’s Injection, USP. When administered through a
Y-site, Tigecycline For Injection is compatible with the following drugs or diluents when
used with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP:
amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer’s, lidocaine
HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA
formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.

Drug Incompatibilities
The following drugs should not be administered simultaneously through the same Y-site as
Tigecycline For Injection amphotericin B, amphotericin B lipid complex, diazepam,
esomeprazole and omeprazole.

In clinical studies in complicated skin and soft tissue infections (cSSTI), complicated intraabdominal
infections (cIAI), diabetic foot infections, nosocomial pneumonia and studies in
resistant pathogens, a numerically higher mortality rate among tigecycline treated patients has
been observed as compared to the comparator treatment. The causes of these findings remain
unknown, but poorer efficacy and safety than the study comparators cannot be ruled out.
Superinfection
In clinical trials in cIAI patients, impaired healing of the surgical wound has been associated
with superinfection. A patient developing impaired healing should be monitored for the
detection of superinfection (see section 4.8).
Patients who develop superinfections, in particular nosocomial pneumonia, appear to be
associated with poorer outcomes. Patients should be closely monitored for the development
of superinfection. If a focus of infection other than cSSTI or cIAI is identified after initiation
of tigecycline therapy consideration should be given to instituting alternative antibacterial
therapy that has been demonstrated to be efficacious in the treatment of the specific type of
infection(s) present.
Anaphylaxis
Anaphylaxis/anaphylactoid reactions, potentially life-threatening, have been reported with
tigecycline (see sections 4.3 and 4.8).
Hepatic failure
Cases of liver injury with a predominantly cholestatic pattern have been reported in patients
receiving tigecycline treatment, including some cases of hepatic failure with a fatal outcome.
Although hepatic failure may occur in patients treated with tigecycline due to the underlying
conditions or concomitant medicinal products, a possible contribution of tigecycline should
be considered (see section 4.8).
Tetracycline class antibiotics
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics.
Tigecycline may have adverse reactions similar to tetracycline class antibiotics. Such
reactions may include photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic
action which has led to increased BUN, azotaemia, acidosis, and hyperphosphataemia (see
section 4.8).
Pancreatitis
Acute pancreatitis, which can be serious, has occurred (frequency: uncommon) in association
with tigecycline treatment (see section 4.8). The diagnosis of acute pancreatitis should be
considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory
abnormalities suggestive of acute pancreatitis. Most of the reported cases developed after at
least one week of treatment. Cases have been reported in patients without known risk factors
for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration
should be given to the cessation of the treatment with tigecycline in cases suspected of having
developed pancreatitis.
Coagulopathy
Tigecycline may prolong both prothrombin time (PT) and activated partial thromboplastin
time (aPTT). Additionally, hypofibrinogenaemia has been reported with the use of
tigecycline. Therefore, blood coagulation parameters such as PT or other suitable
anticoagulation test, including blood fibrinogen, should be monitored prior to treatment
initiation with tigecycline and regularly while on treatment. Special care is recommended in
seriously ill patients and in patients also using anticoagulants (see section 4.5).
Underlying diseases
Experience in the use of tigecycline for treatment of infections in patients with severe
underlying diseases is limited.
In clinical trials in cSSTI, the most common type of infection in tigecycline treated-patients
was cellulitis (58.6 %), followed by major abscesses (24.9 %). Patients with severe
underlying disease, such as those that were immunocompromised, patients with decubitus
ulcer infections, or patients that had infections requiring longer than 14 days of treatment (for
example, necrotizing fasciitis), were not enrolled. A limited number of patients were enrolled
with co-morbid factors such as diabetes (25.8 %), peripheral vascular disease (10.4 %),
intravenous substance abuse (4.0 %), and HIV-positive infection (1.2 %). Limited experience
is also available in treating patients with concurrent bacteraemia (3.4 %). Therefore, caution
is advised when treating such patients. The results in a large study in patients with diabetic
foot infection, showed that tigecycline was less effective than comparator, therefore,
tigecycline is not recommended for use in these patients (see section 4.1).
In clinical trials in cIAI, the most common type of infection in tigecycline-treated patients
was complicated appendicitis (50.3 %), followed by other diagnoses less commonly reported
such as complicated cholecystitis (9.6 %), perforation of intestine (9.6 %), intra-abdominal
abscess (8.7 %), gastric or duodenal ulcer perforation (8.3 %), peritonitis (6.2 %) and
complicated diverticulitis (6.0 %). Of these patients, 77.8 % had surgically-apparent
peritonitis. There were a limited number of patients with severe underlying disease such as
immunocompromised patients, patients with APACHE II scores > 15 (3.3 %), or with
surgically apparent multiple intra-abdominal abscesses (11.4 %). Limited experience is also
available in treating patients with concurrent bacteraemia (5.6 %). Therefore, caution is
advised when treating such patients.
Consideration should be given to the use of combination antibacterial therapy whenever
tigecycline is to be administered to severely ill patients with cIAI secondary to clinically
apparent intestinal perforation or patients with incipient sepsis or septic shock (see section
4.8).
The effect of cholestasis in the pharmacokinetics of tigecycline has not been properly
established. Biliary excretion accounts for approximately 50 % of the total tigecycline
excretion. Therefore, patients presenting with cholestasis should be closely monitored.
Pseudomembranous colitis has been reported with nearly all antibacterial agents and may
range in severity from mild to life threatening. Therefore, it is important to consider this
diagnosis in patients who present with diarrhoea during or subsequent to the administration of
any antibacterial agent (see section 4.8).
The use of tigecycline may result in overgrowth of non-susceptible organisms, including
fungi. Patients should be carefully monitored during therapy (see section 4.8).
Results of studies in rats with tigecycline have shown bone discolouration. Tigecycline may
be associated with permanent tooth discolouration in humans if used during tooth
development (see section 4.8).
Paediatric population
Clinical experience in the use of tigecycline for the treatment of infections in paediatric
patients aged 8 years and older is very limited (see sections 4.8 and 5.1). Consequently, use in
children should be restricted to those clinical situations where no alternative antibacterial
therapy is available.
Nausea and vomiting are very common adverse reactions in children and adolescents (see
section 4.8). Attention should be paid to possible dehydration. Tigecycline should be
preferably administered over a 60-minute length of infusion in paediatric patients.
Abdominal pain is commonly reported in children as it is in adults. Abdominal pain may be
indicative of pancreatitis. If pancreatitis develops, treatment with tigecycline should be
discontinued.
Liver function tests, coagulation parameters, haematology parameters, amylase and lipase
should be monitored prior to treatment initiation with tigecycline and regularly while on
treatment.
Tigecycline for injection should not be used in children under 8 years of age due to the lack
of safety and efficacy data in this age group and because tigecycline may be associated with
permanent teeth discolouration (see sections 4.2 and 4.8).
Excipient information
Tigecycline for injection contains less than 1 mmol sodium (23 mg) per 5 ml of suspension.
Patients on low sodium diets can be informed that this medicinal product is essentially
'sodium free'.

Interaction studies have only been performed in adults.
Concomitant administration of tigecycline and warfarin (25 mg single-dose) to healthy
subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40 % and 23 %,
and an increase in AUC by 68 % and 29 %, respectively. The mechanism of this interaction is
still not elucidated. Available data does not suggest that this interaction may result in
significant INR changes. However, since tigecycline may prolong both prothrombin time
(PT) and activated partial thromboplastin time (aPTT), the relevant coagulation tests should
be closely monitored when tigecycline is co-administered with anticoagulants (see section
4.4). Warfarin did not affect the pharmacokinetic profile of tigecycline.

Tigecycline is not extensively metabolised. Therefore, clearance of tigecycline is not
expected to be affected by active substances that inhibit or induce the activity of the CYP450
isoforms. In vitro, tigecycline is neither a competitive inhibitor nor an irreversible inhibitor of
CYP450 enzymes (see section 5.2).
Tigecycline in recommended dosage did not affect the rate or extent of absorption, or
clearance of digoxin (0.5 mg followed by 0.25 mg daily) when administered in healthy
adults. Digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no
dosage adjustment is necessary when tigecycline is administered with digoxin.
In in vitro studies, no antagonism has been observed between tigecycline and other
commonly used antibiotic classes.
Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less
effective.
Concomitant use of tigecycline and calcineurin inhibitors such as tacrolimus or cyclosporine
may lead to an increase in serum trough concentrations of the calcineurin inhibitors.
Therefore, serum concentrations of the calcineurin inhibitor should be monitored during
treatment with tigecycline to avoid drug toxicity.
Based on an in vitro study tigecycline is a P-gp substrate. Co-administration of P-gp
inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect
the pharmacokinetics of tigecycline (see section 5.2)..

Pregnancy
There are no or limited amount of data from the use of tigecycline in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for
humans is unknown. As it is known for tetracycline class antibiotics, tigecycline may also
induce permanent dental defects (discolouration and enamel defects) and a delay in
ossification processes in foetuses, exposed in utero during the last half of gestation, and in
children under eight years of age due to the enrichment in tissues with a high calcium
turnover and formation of calcium chelate complexes (see section 4.4). Tigecycline should
not be used during pregnancy unless the clinical condition of the woman requires treatment
with tigecycline.

Breast-feeding
It is unknown whether tigecycline/metabolites are excreted in human milk. Available
pharmacodynamic/toxicological data in animals have shown excretion of
tigecycline/metabolites in milk (see section 5.3). A risk to the newborns/infants cannot be
excluded. A decision must be made whether to discontinue breast-feeding or to
discontinue/abstain from tigecycline therapy taking into account the benefit of breast-feeding
for the child and the benefit of therapy for the woman.

Fertility
Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human
daily dose based on AUC. In female rats, there were no compound-related effects on ovaries
oroestrus cycles at exposures up to 4.7 times the human daily dose based on AUC.

Dizziness may occur and this may have an effect on driving and use of machines (see section
4.8)

Description of selected adverse reactions
Antibiotic class effects
Pseudomembranous colitis which may range in severity from mild to life threatening (see
section 4.4).
Overgrowth of non-susceptible organisms, including fungi (see section 4.4).
Tetracycline class effects
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics.
Tetracycline class adverse reactions may include photosensitivity, pseudotumour cerebri,
pancreatitis, and anti-anabolic action which has led to increased BUN, azotaemia, acidosis,
and hyperphosphataemia (see section 4.4).
Tigecycline may be associated with permanent tooth discolouration if used during tooth
development (see section 4.4).
In Phase 3 and 4 cSSTI and cIAI clinical studies, infection-related serious adverse reactions
were more frequently reported for subjects treated with tigecycline (7.1 %) vs comparators
(5.3 %). Significant differences in sepsis/septic shock with tigecycline (2.2 %) vs
comparators (1.1 %) were observed.
AST and ALT abnormalities in tigecycline-treated patients were reported more frequently in
the post therapy period than in those in comparator-treated patients, which occurred more
often on therapy.
In all Phase 3 and 4 (cSSTI and cIAI) studies, death occurred in 2.4 % (54/2216) of patients
receiving tigecycline and 1.7% (37/2206) of patients receiving active comparators.
Paediatric population
Very limited safety data were available from two PK studies (see section 5.2). No new or
unexpected safety concerns were observed with tigecycline in these studies.
In an open-label, single ascending dose PK study, the safety of tigecycline was investigated
in 25 children aged 8 to 16 years who recently recovered from infections. The adverse
reaction profile of tigecycline in these 25 subjects was generally consistent with that in
adults.
The safety of tigecycline was also investigated in an open-label, ascending multi-dose PK
study in 58 children aged 8 to 11 years with cSSTI (n=15), cIAI (n=24) or communityacquired
pneumonia (n=19). The adverse reaction profile of tigecycline in these 58 subjects
was generally consistent with that in adults, with the exception of nausea (48.3 %), vomiting
(46.6 %) and elevated lipase in serum (6.9 %) which were seen at greater frequencies in
children than in adults.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any
possible side effects not listed in this leaflet. You can also report side effects directly (see
details below). By reporting side effects you can help provide more information on the safety
of this medicine.
Reporting of any side effect(s):
If you get any side effects, talk to your or pharmacist. This includes any possible side
effects not listed in this leaflet
- Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
Other GCC States: Please contact the relevant competent authority.

No specific information is available on the treatment of overdosage. Intravenous
administration of tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers
resulted in an increased incidence of nausea and vomiting. Tigecycline is not removed in
significant quantities by haemodialysis.

Pharmacotherapeutic group: Antibacterials for systemic use, tetracyclines, ATC code:
J01AA12.
Mechanism of action
Tigecycline, a glycylcycline antibiotic, inhibits protein translation in bacteria by binding to
the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site
of the ribosome. This prevents incorporation of amino acid residues into elongating peptide
chains.
In general, tigecycline is considered bacteriostatic. At 4 times the minimum inhibitory
concentration (MIC), a 2-log reduction in colony counts was observed with tigecycline
against Enterococcus spp., Staphylococcus aureus, and Escherichia coli.
Mechanism of resistance
Tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal
protection and efflux. Cross-resistance between tigecycline and minocycline-resistant isolates
among the Enterobacteriaceae due to multi-drug resistance (MDR) efflux pumps has been
shown. There is no target-based cross-resistance between tigecycline and most classes of
antibiotics.
Tigecycline is vulnerable to chromosomally-encoded multi-drug efflux pumps
of Proteeae and Pseudomonas aeruginosa. Pathogens of the
family Proteeae (Proteus spp., Providencia spp., and Morganella spp.) are generally less
susceptible to tigecycline than other members of the Enterobacteriaceae. Decreased
susceptibility in both groups has been attributed to the overexpression of the non-specific
AcrAB multi-drug efflux pump. Decreased susceptibility in Acinetobacter baumannii has
been attributed to the overexpression of the AdeABC efflux pump.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European
Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
Staphylococcus spp. S ≤ 0.5 mg/L and R > 0.5 mg/L
Streptococcus spp. other than S. pneumoniae S ≤ 0.25 mg/L and R > 0.5 mg/L
Enterococcus spp. S ≤ 0.25 mg/L and R > 0.5 mg/L
Enterobacteriaceae S ≤ 1(^) mg/L and R > 2 mg/L
(^)Tigecycline has decreased in vitro activity against Proteus, Providencia,
and Morganella spp.
For anaerobic bacteria there is clinical evidence of efficacy in polymicrobial intra-abdominal
infections, but no correlation between MIC values, PK/PD data and clinical outcome.
Therefore, no breakpoint for susceptibility is given. It should be noted that the MIC

distributions for organisms of the genera Bacteroides and Clostridium are wide and may
include values in excess of 2 mg/L tigecycline.
There is limited evidence of the clinical efficacy of tigecycline against enterococci. However,
polymicrobial intra-abdominal infections have shown to respond to treatment with tigecycline
in clinical trials.
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected
species, and local information on resistance is desirable, particularly when treating severe
infections. As necessary, expert advice should be sought when the local prevalence of
resistance is such that the utility of the agent in at least some types of infections is
questionable.

Efficacy data above shown should be viewed with caution as concomitant antibiotics were allowed in this study. In addition, the small number of patients should also be taken into consideration.

Absorption
Tigecycline is administered intravenously and therefore has 100 % bioavailability.

Distribution
The in vitro plasma protein binding of tigecycline ranges from approximately 71 % to 89 % at concentrations observed in clinical studies (0.1 to 1.0 mcg/ml). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving single or multiple doses of 14C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone marrow, salivary glands, thyroid gland, spleen, and kidney. In humans, the steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume and concentrates into tissues.

No data are available on whether tigecycline can cross the blood-brain barrier in humans. In clinical pharmacology studies using the therapeutic dosage regimen of 100 mg followed by 50 mg q12h, serum tigecycline steady-state Cmax was 866±233 ng/ml for 30-minute infusions and 634±97 ng/ml for 60-minute infusions. The steady-state AUC0-12h was 2349±850 ng•h/ml.

Biotransformation
On average, it is estimated that less than 20 % of tigecycline is metabolised before excretion. In healthy male volunteers, following the administration of 14C-tigecycline, unchanged

tigecycline was the primary 14C-labelled material recovered in urine and faeces, but a glucuronide, an N-acetyl metabolite and a tigecycline epimer were also present.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 by competitive inhibition. In addition, tigecycline did not show NADPH-dependency in the inhibition of CYP2C9, CYP2C19, CYP2D6 and CYP3A, suggesting the absence of mechanism-based inhibition of these CYP enzymes.

Elimination
The recovery of the total radioactivity in faeces and urine following administration of 14C-tigecycline indicates that 59 % of the dose is eliminated by biliary/faecal excretion, and 33 % is excreted in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

The total clearance of tigecycline is 24 L/h after intravenous infusion. Renal clearance is approximately 13 % of total clearance. Tigecycline shows a polyexponential elimination from serum with a mean terminal elimination half-life after multiple doses of 42 hours although high interindividual variability exists.

In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not a P-glycoprotein (P-gp) inhibitor. This in vitro information is consistent with the lack of effect of tigecycline on digoxin clearance noted in the in vivo drug interaction study described above (see section 4.5).

Tigecycline is a substrate of P-gp based on an in vitro study using a cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known. Co-administration of P-gp inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of tigecycline.

Special populations
Hepatic impairment
The single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25 % and 55 % and the half-life of tigecycline was prolonged by 23 % and 43 % in patients with moderate or severe hepatic impairment (Child Pugh B and C), respectively (see section 4.2).

Renal impairment

The single dose pharmacokinetic disposition of tigecycline was not altered in patients with renal insufficiency (creatinine clearance <30 ml/min, n=6). In severe renal impairment, AUC was 30 % higher than in subjects with normal renal function (see section 4.2).

Elderly
No overall differences in pharmacokinetics were observed between healthy elderly subjects and younger subjects (see section 4.2).

Paediatric population
Tigecycline pharmacokinetics was investigated in two studies. The first study enrolled children aged 8-16 years (n=24) who received single doses of tigecycline (0.5, 1, or 2 mg/kg, up to a maximum dose of 50 mg, 100 mg, and 150 mg, respectively) administered intravenously over 30 minutes. The second study was performed in children aged 8 to 11 years who received multiple doses of tigecycline (0.75, 1, or 1.25 mg/kg up to a maximum dose of 50 mg) every 12 hours administered intravenously over 30 minutes. No loading dose was administered in these studies. Pharmacokinetic parameters are summarised in the table below.

In repeated dose toxicity studies in rats and dogs, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, and adverse renal and gastrointestinal effects have been seen with tigecycline at exposures of 8 and 10 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after two weeks of dosing.

Bone discolouring was observed in rats which was not reversible after two weeks of dosing. Results of animal studies indicate that tigecycline crosses the placenta and is found in foetal tissues. In reproduction toxicity studies, decreased foetal weights in rats and rabbits (with associated delays in ossification) and foetal loss in rabbits have been observed with tigecycline. Tigecycline was not teratogenic in the rat or rabbit. Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or oestrus cycles at exposures up to 4.7 times the human daily dose based on AUC.

Results from animal studies using 14C-labelled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in the nursing pups as a result of exposure via maternal milk.

Lifetime studies in animals to evaluate the carcinogenic potential of tigecycline have not been performed, but short-term genotoxicity studies of tigecycline were negative.

Bolus intravenous administration of tigecycline has been associated with a histamine response in animal studies. These effects were observed at exposures of 14 and 3 times the human daily dose based on the AUC in rats and dogs respectively.

No evidence of photosensitivity was observed in rats following administration of tigecycline.

Lactose Monohydrate USP-NF
Hydrochloric Acid USP-NF
Sodium Hydroxide USP-NF
Water for Injection USP

The following active substances should not be administered simultaneously through the same Y-site as tigecycline: Amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole, omeprazole and intravenous solutions that could result in an increase of pH above 7. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Store below 25°C prior to reconstitution. The reconstituted solution of Tigecycline for injection, USP may be stored at refrigerator condition.

Alternatively, tigecycline for injection mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag.

Each 5 mL USP Type-I clear glass tubular Lyo Vial contains 50 mg of Tigecycline

The powder should be reconstituted with 5.3 ml of sodium chloride 9 mg/ml (0.9 %) solution
for injection, dextrose 50 mg/ml (5 %) solution for injection, or Lactated Ringer's solution for
injection to achieve a concentration of 10 mg/ml of tigecycline. The vial should be gently
swirled until the medicinal product is dissolved. Thereafter, 5 ml of the reconstituted solution
should be immediately withdrawn from the vial and added to a 100 ml intravenous bag for
infusion or other suitable infusion container (e.g., glass bottle).
For a 100 mg dose, reconstitute using two vials into a 100 ml intravenous bag or other
suitable infusion container (e.g., glass bottle). Note: The vial contains a 6 % overage. Thus, 5
ml of reconstituted solution is equivalent to 50 mg of the active substance. The reconstituted
solution should be yellow to orange in colour; if not, the solution should be discarded.
Parenteral products should be inspected visually for particulate matter and discolouration
(e.g., green or black) prior to administration.
Tigecycline should be administered intravenously through a dedicated line or through a Ysite.
If the same intravenous line is used for sequential infusion of several active substances,
the line should be flushed before and after infusion of tigecycline with either sodium chloride
9 mg/ml (0.9 %) solution for injection or dextrose 50 mg/ml (5 %) solution for injection.
Injection should be made with an infusion solution compatible with tigecycline and any other
medicinal product(s) via this common line (see section 6.2)
This medicinal product is for single use only; any unused medicinal product or waste material
should be disposed of in accordance with local requirements.
Compatible intravenous solutions include: sodium chloride 9 mg/ml (0.9 %) solution for
injection, dextrose 50 mg/ml (5 %) solution for injection, and Lactated Ringer's solution for
injection.
When administered through a Y-site, compatibility of tigecycline diluted in sodium chloride
0.9 % for injection is demonstrated with the following medicinal products or diluents:
amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer's, lidocaine
HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA
formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.