- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe recommended dose for adults is an initial dose of 100 mg followed by 50 mg every 12 hours for 5 to 14 days.The duration of therapy should be guided by the severity, site of the infection, and the patient's clinical response.
Hepatic insufficiencyNo dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B).In patients (including paediatrics) with severe hepatic impairment (Child Pugh C), the dose of Tygacil should be reduced by 50%. Adult dose should be reduced to 25 mg every 12 hours following the 100 mg loading dose. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see sections 4.4 and 5.2).
Renal insufficiencyNo dosage adjustment is necessary in patients with renal impairment or in patients undergoing haemodialysis (see section 5.2).
Elderly patientsNo dosage adjustment is necessary in elderly patients (see section 5.2). Paediatric populationTygacil is only to be used to treat patients aged 8 years and older after consultation with a physician with appropriate experience in the management of infectious diseases. Children aged 8 to <12 years: 1.2 mg/kg of tigecycline every 12 hours intravenously to a maximum dose of 50 mg every 12 hours for 5 to 14 days. Adolescents aged 12 to <18 years: 50 mg of tigecycline every 12 hours for 5 to 14 days. Children under 8 years of age: Tygacil should not be used in children under 8 years of age due to the lack of data on safety and efficacy in this age group and because of teeth discolouration (see sections 4.4 and 5.1).
Method of administration:Tygacil is administered only by intravenous infusion over 30 to 60 minutes (see sections 4.4 and 6.6).Tigecycline should be preferably administered over a 60-minute length of infusion in paediatric patients (see section 4.4).For instructions on reconstitution & dilution of the medicinal product before administration, see section 6.6.
Paediatric populationClinical 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.Tygacil 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).
PregnancyThere are no adequate data from the use of tigecycline in pregnant women. Results from animal studies have shown tigecycline may cause foetal harm when administered during pregnancy (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 clearly necessary.
Breast feedingIt is not known whether tigecycline/metabolites are excreted in human milk. In animal studies tigecycline is excreted into milk of lactating rats. Because a potential risk to the breast-feeding infant cannot be ruled out, when treating with tigecycline, caution should be exercised and interruption of breast-feeding should be considered (see section 5.3).
FertilityTigecycline 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.
Infections and infestations:Common: Sepsis/septic shock, pneumonia, abscess, infections
Blood and the lymphatic system disorders:Common: Prolonged activated partial thromboplastin time (aPTT), Prolonged prothrombin time (PT)Uncommon: Thrombocytopenia, Increased International Normalised Ratio (INR)
Immune system disorders:Not known: Anaphylaxis/anaphylactoid reactions (see sections 4.3 and 4.4)
Metabolism and nutrition disorders:Common: Hypoglycaemia, hypoproteinaemia
Nervous system disorders:Common: Dizziness
Vascular disorders:Common: PhlebitisUncommon: Thrombophlebitis
Gastrointestinal disorders:Very common: Nausea, vomiting, diarrhoeaCommon: Abdominal pain, dyspepsia, anorexiaUncommon: Acute pancreatitis (see section 4.4)
Hepatobiliary disorders:Common: Elevated aspartate aminotransferase (AST) in serum, and elevated alanine aminotransferase (ALT) in serum, hyperbilirubinaemiaUncommon: Jaundice, liver injury, mostly cholestaticNot known: Hepatic failure (see section 4.4)
Skin and subcutaneous tissue disorders:Common: Pruritus, rashNot known: Severe skin reactions, including Stevens-Johnson Syndrome
General disorders and administration site conditions:Common: Impaired healing, injection site reaction, headacheUncommon:,Injection site inflammation, injection site pain, injection site oedema, injection site phlebitis
Investigations:Common: Elevated amylase in serum, increased blood urea nitrogen (BUN)c. Description of selected adverse reactionsAntibiotic 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 events 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 Tygacil-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 comparator drugs.
Paediatric populationVery 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 community-acquired 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 suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard
Mechanism of actionTigecycline, 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 resistanceTigecycline 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 multidrug 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.
BreakpointsMinimum 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/LStreptococcus spp. other than S. pneumoniae S ≤ 0.25 mg/L and R > 0.5 mg/LEnterococcus spp. S ≤ 0.25 mg/L and R > 0.5 mg/LEnterobacteriaceae 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.
SusceptibilityThe 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.
|Commonly Susceptible Species|
|Gram-positive AerobesEnterococcus spp.Staphylococcus aureus*Staphylococcus epidermidisStaphylococcus haemolyticusStreptococcus agalactiae* Streptococcus anginosus group* (includes S. anginosus, S. intermedius and S. constellatus)Streptococcus pyogenes* Viridans group streptococci Gram-negative AerobesCitrobacter freundii*Citrobacter koseriEscherichia coli*Klebsiella oxytoca*AnaerobesClostridium perfringensPeptostreptococcus spp.Prevotella spp.|
|Species for which acquired resistance may be a problem|
|Gram-negative AerobesAcinetobacter baumanniiBurkholderia cepaciaEnterobacter aerogenesEnterobacter cloacae*Klebsiella pneumoniae*Morganella morganiiProteus spp. Providencia spp. Serratia marcescensStenotrophomonas maltophiliaAnaerobesBacteroides fragilis group|
|Inherently resistant organisms|
|Gram-negative AerobesPseudomonas aeruginosa|
Cardiac ElectrophysiologyNo significant effect of a single intravenous dose of tigecycline 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.
Paediatric populationIn an open-label, ascending multiple-dose study, 39 children aged 8 to 11 years with cIAI or cSSTI were administered tigecycline (0.75, 1, or 1.25 mg/kg). All patients received IV tigecycline for a minimum of 3 consecutive days to a maximum of 14 consecutive days, with the option to be switched to an oral antibiotic on or after day 4. Clinical cure was assessed between 10 and 21 days after the administration of the last dose of treatment. The summary of clinical response in the modified intent-to-treat (mITT) population results is shown in the following table.
|Clinical Cure, mITT Population|
|0.75 mg/kg||1 mg/kg||1.25 mg/kg|
|Indication||n/N (%)||n/N (%)||n/N (%)|
|cIAI||6/6 (100.0)||3/6 (50.0)||10/12 (83.3)|
|cSSTI||3/4 (75.0)||5/7 (71.4)||2/4 (50.0)|
|Overall||9/10 (90.0)||8/13 (62.0 %)||12/16 (75.0)|
AbsorptionTigecycline is administered intravenously and therefore has 100 % bioavailability.
DistributionThe 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 ngh/ml.
BiotransformationOn 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.
EliminationThe 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.
Hepatic InsufficiencyThe 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 InsufficiencyThe 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 PatientsNo overall differences in pharmacokinetics were observed between healthy elderly subjects and younger subjects (see section 4.2).
Paediatric PopulationTigecycline 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.
|Dose Normalized to 1 mg/kg Mean ± SD Tigecycline Cmax and AUC in Children|
|Age (yr)||N||Cmax (ng/mL)||AUC (ngh/mL)*|
|8 11||8||3881 ± 6637||4034 ± 2874|
|12 - 16||16||8508 ± 11433||7026 ± 4088|
|8 - 11||42||1911 ± 3032||2404 ± 1000|
|* single dose AUC0-∞, multiple dose AUC0-12h|
GenderThere were no clinically relevant differences in the clearance of tigecycline between men and women. AUC was estimated to be 20 % higher in females than in males.
RaceThere were no differences in the clearance of tigecycline based on race.
WeightClearance, weight-normalised clearance, and AUC were not appreciably different among patients with different body weights, including those weighing ≥ 125 kg. AUC was 24 % lower in patients weighing ≥ 125 kg. No data is available for patients weighing 140 kg and more.
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