Tacyl 50,0 mg Solution

TACYL 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 TACYL is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of TACYL should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment with TACYL 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 TACYL 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 TACYL in patients with severe hepatic impairment (Child Pugh C), the dose of TACYL 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 children: Safety and effectiveness in patients under 18 years of age have not been established. Therefore, use in patients under 18 years of age is not recommended (see section 4.4).

Use in elderly: No dosage adjustment is necessary in elderly patients (see section 4.4 and 4.8).

Race and gender: No dosage adjustment is necessary based on race or gender (see section 5.2).

Method of administration: TACYL is administered only by intravenous infusion over 30 to 60 minutes (see sections 4.4 and 6.6). For instructions on reconstitution & dilution of TACYL before administration, see section 6.6.

• Hypersensitivity to tigecycline or to any of the excipients listed in section 6.1.
• Patients hypersensitive to tetracycline class antibiotics may be hypersensitive to tigecycline.
• 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 (e.g. TACYL) 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: From the studies conducted, 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 TACYL 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 TACYL due to the underlying conditions or concomitant medicines, a possible contribution of TACYL should be considered (see section 4.8).

Tetracycline class antibiotics: Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. TACYL 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 TACYL 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 TACYL discontinuation. Consideration should be given to the cessation of the treatment with TACYL in cases suspected of having developed pancreatitis.

Underlying diseases: Experience in the use of TACYL for treatment of infections in patients with severe underlying diseases is limited. Consideration should be given to the use of combination antibacterial therapy whenever TACYL 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.

Prothrombin time or other suitable anticoagulation test should be used to monitor patients if TACYL is administered with anticoagulants (see section 4.5).

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 TACYL 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. TACYL 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. TACYL should be preferably administered over a 60-minute length of infusion in paediatric patients. Abdominal pain is frequently 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 TACYL and regularly while on treatment. TACYL should not be used in children 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).

Concomitant administration of TACYL (100 mg followed by 50 mg every 12 hours) 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. TACYL did not significantly alter the effects of warfarin on increased international normalised ratio (INR). In addition, warfarin did not affect the pharmacokinetic profile of TACYL. However, prothrombin time or other suitable anticoagulation test should be monitored if TACYL is administered with warfarin.

TACYL 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).

TACYL (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg every 24 hours) were co-administered to healthy subjects in a medicine interaction study. TACYL 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. In addition, digoxin did not affect the pharmacokinetic profile of TACYL. Therefore, no dosage adjustment is necessary when TACYL is administered with digoxin.

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. Based on an in vitro study tigecycline is a P-gp substrate. Co-administration of P-gp inhibitors (e.g., ketoconazole or ciclosporin) 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 TACYL in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). TACYL is contraindicated during pregnancy.

Breastfeeding: 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). TACYL is contraindicated during breastfeeding.

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 or oestrus 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).

Summary of safety profile: The most frequent medicine-related treatment emergent adverse reactions were reversible nausea and vomiting, which usually occurred early (on treatment days 1-2) and were generally mild or moderate in severity.

Tabulated list of adverse reactions:

SYSTEM ORGAN

FREQUENT: LESS FREQUENT: FREQUENCY CLASS: UNKNOWN:

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)

Hepato-biliary disorders: Elevated aspartate aminotransferase (AST) in serum, and elevated alanine aminotransferase (ALT) in serum, hyperbilirubinaemia Jaundice, liver injury, mostly cholestatic (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 anti-anabolic action which has led to increased BUN, azotaemia, acidosis, and hyperphosphataemia (see section 4.4). TACYL may be associated with permanent tooth discolouration if used during tooth development (see section 4.4).

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.

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. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u20186.04 Adverse Drug Reactions Reporting Formu2019, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

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