4.1. Therapeutic indications

Tigecycline is indicated in adults and in children from the age of eight years for the treatment of the following infections (see sections 4.4 and 5.1):

• Complicated skin and soft tissue infections (cSSTI), excluding diabetic foot infections (see section 4.4)

• Complicated intra-abdominal infections (cIAI)

Tigecycline should be used only in situations where other alternative antibiotics are not suitable (see sections 4.4, 4.8 and 5.1).

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

4.2. Posology and method of administration

Posology

Adults

The recommended dose is an initial dose of 100 mg followed by 50 mg every 12 hours for 5 to 14 days.

Children and adolescents (8 to 17 years of age)

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.

The duration of therapy should be guided by the severity, site of the infection, and the patient's clinical response.

Elderly

No dosage adjustment is necessary in elderly patients (see section 5.2).

Hepatic impairment

No 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 tigecycline 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 impairment

No dosage adjustment is necessary in patients with renal impairment or in patients undergoing haemodialysis (see section 5.2).

Paediatric population

The safety and efficacy of tigecycline in children under 8 years of age have not been established. No data are available. Tigecycline should not be used in children aged under 8 years because of teeth discolouration (see sections 4.4 and 5.1)

Method of administration:

Tigecycline 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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients hypersensitive to tetracycline class antibiotics may be hypersensitive to tigecycline.

4.4. Special warnings and precautions for use

In clinical studies in complicated skin and soft tissue infections (cSSTI), complicated intra-abdominal 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 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 section 4.8).

Excipient information

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

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).

4.6. Fertility, pregnancy and lactation

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 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

The effects of tigecycline on fertility in humans have not been studied. Nonclinical studies conducted with tigecycline in rats do not indicate harmful effects with respect to fertility or reproductive performance. 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 (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

The total number of cSSTI and cIAI patients treated with tigecycline in Phase 3 and 4 clinical studies was 2,393.

In clinical trials, the most common medicinal product-related treatment emergent adverse reactions were reversible nausea (21 %) and vomiting (13 %), which usually occurred early (on treatment days 1-2) and were generally mild or moderate in severity.

Adverse reactions reported with tigecycline, including clinical trials and post-marketing experience, are tabulated below.

Tabulated list of adverse reactions

System Organ Class

Very Common

≥ 1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1,000 to < 1/100

Rare

≥1/10,000 to <1/1,000

Frequency not known

(cannot be estimated from the available data)

Infections and infestations

sepsis/septic shock, pneumonia, abscess, infections

Blood and lymphatic system disorders

prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT)

thrombocytopenia, increased international normalised ratio (INR)

hypofibrinogenaemia

Immune system disorders

anaphylaxis/anaphylactoid reactions* (see sections 4.3 and 4.4)

Metabolism and nutrition disorders

hypoglycaemia, hypoproteinaemia

Nervous system disorders

dizziness

Vascular disorders

phlebitis

thrombophlebitis

Gastrointestinal disorders

nausea, vomiting, diarrhoea

abdominal pain, dyspepsia, anorexia

acute pancreatitis (see section 4.4)

Hepatobiliary disorders

elevated aspartate aminotransferase (AST) in serum, and elevated alanine aminotransferase (ALT) in serum, hyperbilirubinaemia

jaundice, liver injury, mostly cholestatic

hepatic failure* (see section 4.4)

Skin and subcutaneous tissue disorders

pruritus, rash

severe skin reactions, including Stevens-Johnson Syndrome*

General disorders and administration site conditions

impaired healing, injection site reaction, headache

injection site inflammation, injection site pain, injection site oedema, injection site phlebitis

Investigations

elevated amylase in serum, increased blood urea nitrogen (BUN)

*ADR identified post-marketing

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 antianabolic 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 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 reactions

Reporting 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.