Tizeg 50 mg Powder for solution for infusion

TIZEG is indicated for treatment of the following severe life-threatening infections in adults:

• Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group (includes S.anginosus, S.intermedius, and S. constellatus), Streptococcus pyogenes and Bacteroides fragilis.
• Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus group (includes S.anginosus, S.intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Posology

The recommended dosage regimen for TIZEG is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of TIZEG should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment with TIZEG for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patientu2019s clinical and bacteriological progress.

Use in patients with renal impairment

No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing haemodialysis. (See section 5.2, Renal insufficiency).

Use in patients with hepatic impairment

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Based on the pharmacokinetic profile of tigecycline in patients with severe hepatic impairment (Child Pugh C), the dose of TIZEG should be altered to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response. (See section 5.2, Hepatic insufficiency.)

Use in elderly

No dosage adjustment is necessary in elderly patients. (See section 4.4, Elderly Use).

Race and gender

No dosage adjustment is necessary based on race or gender. (See section 5.2).

Paediatric Population

Safety and effectiveness in patients under 18 years of age have not been reported. Therefore, use in patients under 18 years of age is not recommended. (See section 4.4).

Method of administration

Tigecycline is to be administered only by intravenous infusion. For instructions on reconstitution and dilution of the medicine before administration, see section 6.6.

• Hypersensitivity to the active substance tigecycline or to any of the excipients listed in section 6.1.
• Pregnancy and Lactation

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 reported 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 reported 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 reported 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 medicines, 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. TIZEG 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 (blood urea nitrogen), azotaemia, acidosis, and hyperphosphataemia (see section 4.8). Therefore, TIZEG should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics.

Pancreatitis

Acute pancreatitis, which can be serious, has been reported (frequency: less frequent) in association with TIZEG 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 treatment with tigecycline in cases suspected of having developed pancreatitis.

Coagulopathy

TIZEG 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 TIZEG 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

Reported experience in the use of TIZEG for treatment of infections in patients with severe underlying diseases is limited. In reported clinical trials in cSSTI, the most common type of infection in tigecycline treated-patients was cellulitis, followed by major abscesses. 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, peripheral vascular disease, intravenous substance abuse, and HIV-positive infection. Limited reported experience is also available in treating patients with concurrent bacteraemia. Therefore, caution is advised when treating such patients. The results in a large study in patients with diabetic foot infection, reported that tigecycline was less effective than comparator, therefore, tigecycline is not recommended for use in these patients.

In reported clinical trials in cIAI, the most common type of infection in tigecycline-treated patients was complicated appendicitis, followed by other diagnoses less commonly reported such as complicated cholecystitis, perforation of intestine, intra-abdominal abscess, gastric or duodenal ulcer perforation, peritonitis and complicated diverticulitis. 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, or with surgically apparent multiple intra-abdominal abscesses. Limited reported experience is also available in treating patients with concurrent bacteraemia. Therefore, caution is advised when treating such patients.

Consideration should be given to the use of combination antibacterial therapy whenever TIZEG 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 medicines 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 medicine (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 reported bone discolouration. TIZEG may be associated with permanent tooth discolouration in humans if used during tooth development (see section 4.8).

The safety and efficacy of TIZEG in patients with hospital acquired pneumonia have not been reported. In a study of patients with hospital acquired pneumonia, patients were randomized to receive tigecycline (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received tigecycline reported lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (19.1% versus 11.5%) than the comparator.

Interaction studies have only been performed in adults. Concomitant administration of tigecycline and warfarin (25 mg single-dose) to healthy subjects reported 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 report that this interaction may result in significant INR changes. However, since TIZEG may prolong both prothrombin time (PT) and activated partial thromboplastin time (aPTT), the relevant coagulation tests should be closely monitored when TIZEG is co-administered with anticoagulants (see section 4.4). Warfarin did not affect the pharmacokinetic profile of tigecycline.

In vitro studies in human liver microsomes reported that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome CYP450 isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, TIZEG is not expected to alter the metabolism of medicines metabolized by these enzymes. 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.

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. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. Digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment is necessary when TIZEG is administered with digoxin.

In vitro studies, no antagonism has been reported 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 a reported 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.

Interference with Laboratory and Other Diagnostic Tests

There are no reported drug-laboratory test interactions.

Pregnancy

TIZEG may cause foetal harm when administered to a pregnant woman. Results of animal studies reported that tigecycline crosses the placenta and is found in foetal tissues. There are no reported studies of TIZEG in pregnant women. TIZEG should not be used during pregnancy (See section 4.3). TIZEG has not been studied for use during labour and delivery.

Breast-feeding

It is unknown whether tigecycline/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have reported excretion of tigecycline/metabolites in milk. A risk to the newborns/infants cannot be excluded.

Fertility

The effects of tigecycline on fertility in humans have not been studied. Tigecycline reported to not affect mating or fertility in rats. In female rats, no compound-related effects on ovaries or oestrus cycles were reported 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).

Summary of safety profile

In clinical trials, the most frequent medicine-related treatment emergent adverse reactions reported were reversible nausea and vomiting, 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

• Frequent: sepsis/septic shock, pneumonia, abscess, infections
• Less frequent: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), thrombocytopenia, increased international normalised ratio (INR), hypofibrinogenaemia
• Frequency not known (cannot be estimated from the reported data): anaphylaxis/anaphylactoid reactions* (see sections 4.3 and 4.4), hypoglycaemia, bilirubinaemia, hypoproteinaemia, dizziness, phlebitis, thrombophlebitis, nausea, vomiting, diarrhea, abdominal pain, dyspepsia, anorexia, acute pancreatitis (see section 4.4), 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), hepatic cholestasis, pruritus, rash, severe skin reactions, including Stevens-Johnson Syndrome*, impaired healing, injection site reaction, headache, injection site inflammation, injection site pain, injection site reaction, injection site oedema, injection site phlebitis, 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 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).

Table: Patients with Adverse events with outcome of death by Infection type

Tigecycline Comparator Risk Difference *

Infection Type % % % (95 % CI)

cSSSI 1.1 0.2 0.9 (-0.3; 2.2)

cIAI 2.9 2.1 0.9 (-0.8; 2.6)

CAP 2.8 2.6 0.2 (-2.3; 2.7)

HAP 13.9 12.0 1.9 (-2.6; 6.4)

Non-VAP a 11.9 12.2 -0.3 (-5.4; 4.9)

VAP a 19.1 11.5 7.6 (-2.0; 16.9)

CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia

*The difference between the percentage of patients who died in tigecycline and comparator treatment groups.

a These are the subgroups of the HAP population

The frequent drug-related treatment emergent events reported in patients treated with TIZEG were nausea 20.4 (12.9% mild; 6.6% moderate; 0.8% Severe) and vomiting 13.5% (8.3% mild; 4.5% moderate; 0.6% severe). In general, nausea or vomiting occurred early (days 1 - 2).

Discontinuation from TIZEG was most frequently associated with nausea (1.3%) and vomiting (1.0%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

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