Gaticil Iv 50 mg Powder for solution for infusion.

GATICIL IV 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 uniforms, Bacteroides vulgatus, Clostridium perfringens and Peptostreptococcus micros.

Posology

The recommended dosage regimen for GATICIL IV is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of GATICIL IV should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment with GATICIL IV 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.

Special populations

Patients with renal impairment

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

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 GATICIL IV in patients with severe hepatic impairment (Child Pugh C), the dose of GATICIL IV 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).

Use in elderly

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

Race and gender

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

Pediatric population

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).

Method of administration

Intravenous infusion. GATICIL IV must be reconstituted, transferred and further diluted for I.V. infusion. For instructions on reconstitution & dilution of the medicinal product before administration, see section 6.6.

• Hypersensitivity to tigecycline or to any of the ingredients of GATICIL IV (see section 6.1).
• Pregnancy and lactation (see section 4.6).

Superinfection

Use of GATICIL IV may result in overgrowth of non-susceptible organisms, including fungi. Patients, especially those developing impaired healing (e.g. of a surgical wound), should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. 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 skin and soft tissue infection (cSSTI) or intra-abdominal infections (cIAI) is identified after initiation of GATICIL IV 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 have been reported with nearly all antibacterial medicines, including GATICIL IV, and may be life-threatening.

Hepatic failure

Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Although hepatic failure may occur in patients treated with GATICIL IV due to the underlying conditions or concomitant medicinal products, a possible contribution of GATICIL IV should be considered (see section 4.8).

Tetracycline class antibiotics

Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics, such as GATICIL IV, and may have similar side effects. Such effects may include photosensitivity, pseudotumour cerebri, and anti-anabolic action (which has led to increased blood urea nitrogen (BUN), azotaemia, acidosis, and hyperphosphataemia). Therefore GATICIL IV should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics.

Pancreatitis

As with tetracycline, pancreatitis has been reported with the use of GATICIL IV. The diagnosis of acute pancreatitis should be considered in patients taking GATICIL IV who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Most cases of pancreatitis develop after at least one week of treatment and can also develop without known risk factors for pancreatitis. Patients usually improve after GATICIL IV discontinuation. Consideration should be given to the cessation of treatment with GATICIL IV in patients 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, as in GATICIL IV. Therefore, blood coagulation parameters such as PT or other suitable anticoagulation test, including blood fibrinogen, should be monitored prior to treatment initiation with GATICIL IV 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, as in GATICIL IV, for treatment of infections in patients with severe underlying diseases is limited. Caution is advised when treating patients with underlying conditions such as diabetes, peripheral vascular disease, intravenous substance abuse, HIV-positive infection, concurrent bacteraemia, patients with APACHE II scores > 15, surgically apparent multiple intra-abdominal abscesses and immunocompromised patients. Consideration should be given to the use of combination antibacterial therapy whenever GATICIL IV 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, as in GATICIL IV 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

Pseudomembranous colitis has been reported with the use of tigecycline, as in GATICIL IV. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of GATICIL IV.

Intra-abdominal infections

Caution should be exercised when considering GATICIL IV monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. Intestinal perforations and sepsis/septic shock have been reported in this patient group, however the relationship of this outcome to GATICIL IV treatment has not been established.

Hospital acquired pneumonia

The safety and efficacy of GATICIL IV in patients with hospital acquired pneumonia have not been established.

Tooth discolouration

GATICIL IV may be associated with permanent tooth discolouration during tooth development.

Abuse and dependence

Medicine abuse and dependence have not been demonstrated and are unlikely.

Elderly patients

No unexpected overall differences in safety or effectiveness have been observed between older patients (> 65 years old) and younger patients, however greater sensitivity to side effects by some elderly patients cannot be ruled out.

Pediatric population

Safety and effectiveness in patients under 18 years of age have not been established. Therefore, use of GATICIL IV in patients under 18 years of age is not recommended.

Calcineurin inhibitors

Concomitant use of GATICIL IV and calcineurin inhibitors such as tacrolimus or cyclosporin 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 GATICIL IV to avoid medicine toxicity.

Warfarin

Concomitant administration of GATICIL IV (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. GATICIL IV does not significantly alter the effects of warfarin on increased international normalized ratio (INR). In addition, warfarin does not affect the pharmacokinetic profile of GATICIL IV. However, prothrombin time or other suitable anticoagulation test should be monitored if GATICIL IV is administered with warfarin.

Oral contraceptives

Concurrent use of antibiotics, such as GATICIL IV, with oral contraceptives may render oral contraceptives less effective. Patients should be advised to use additional contraception during treatment with GATICIL IV.

Digoxin

GATICIL IV (100 mg followed by 50 mg every 12 hours) decreases the C max of digoxin (0,5 mg followed by 0,25 mg every 24 hours) were co-administered to healthy subjects in a drug interaction study. GATICIL IV slightly decreased the C max of digoxin by 13 % but did not affect the AUC or clearance of digoxin. This small change in C max does not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin does not affect the pharmacokinetic profile of GATICIL IV. Therefore, no dosage adjustment is necessary when GATICIL IV is administered with digoxin.

CYP 450 isoforms

In vitro studies in human liver microsomes indicate that GATICIL IV does not inhibit metabolism mediated by any of the following 6 cytochrome CYP450 isoforms: 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4. Therefore, GATICIL IV is not expected to alter the metabolism of medicines metabolised by these enzymes. In addition, because GATICIL IV is not extensively metabolised, clearance of GATICIL IV is not expected to be affected by medicines that inhibit or induce the activity of these CYP450 isoforms.

Antibiotic medicines

In in vitro studies, no antagonism has been observed between GATICIL IV and other commonly used antibiotic classes.

P-gp inhibitors and inducers

Based on an in vitro study tigecycline, as in GATICIL IV, is a P-gp substrate. Co-administration of P-gp inhibitors (e.g., ketoconazole or cyclosporin) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of GATICIL IV.

Interference with laboratory and other diagnostic tests

There are no reported medicine-laboratory test interactions.

Contraception in males and females

Women of childbearing potential should ensure effective contraception. For maximal protection, use of additional non-hormonal contraception (e.g. barrier contraceptives) is recommended during treatment and also for some time after the treatment is stopped.

Pregnancy

GATICIL IV may cause foetal harm when administered to a pregnant woman. Results of animal studies indicate that GATICIL IV crosses the placenta and is found in foetal tissues. There are no adequate and well-controlled studies of GATICIL IV in pregnant women, nor its use during labour and delivery.

Breastfeeding

Results from animal studies using 14 C-labeled tigecycline, as in GATICIL IV, indicate that GATICIL IV is excreted readily via the milk of lactating rats. It is not known whether tigecycline is excreted in human milk. GATICIL IV should therefore not be used during pregnancy or lactation (see section 4.3).

GATICIL IV can cause dizziness which may impair the ability to drive and/or operate machinery.

a) Summary of the safety profile

Studies indicate that the most common adverse reactions, nausea and vomiting, occur in early treatment (days 1 and 2), are reversible and mild or moderate in severity.

b) Tabulated list of adverse reactions

System Organ Class

Frequency

Side effects

Infections and Infestations

Frequent

Sepsis/septic shock, abscess, infections

Respiratory, thoracic and mediastinal disorders

Frequent

Pneumonia

Blood and lymphatic system disorders

Frequent

Less frequent

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

Increased international normalised ratio (INR), hypofibrinogenaemia

Immune system disorders

Frequency unknown

Anaphylaxis/anaphylactoid reactions

Metabolism and nutrition disorders

Frequent

Bilirubinaemia, hypoproteinaemia, hypoglycaemia

Nervous system disorders

Frequent

Dizziness

Vascular disorders

Frequent

Less frequent

Phlebitis

Thrombophlebitis

Gastrointestinal disorders

Frequent

Less frequent

Frequency unknown

Nausea, vomiting, diarrhoea, anorexia, abdominal pain, dyspepsia

Acute pancreatitis

Pseudomembranous colitis, tooth discolouration of developing teeth

Hepato-biliary disorders

Frequent

Less frequent

Frequency unknown

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

Jaundice, liver injury, mostly cholestatic

Hepatic cholestasis, hepatic failure

Skin and subcutaneous tissue disorders

Frequent

Frequency unknown

Pruritus, rash

Severe skin reactions including Stevens-Johnson Syndrome

General disorders and administrative site conditions

Frequent

Less frequent

Headache, injection site reaction, impaired healing

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

Investigations

Frequent

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

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 professionals are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8. An email can be sent directly to the company, [email protected] to ensure safety of the product.

Signs and symptoms

No specific information is available on the treatment of overdosage with GATICIL IV. Intravenous administration of GATICIL IV at a single dose of 300 mg over 60 minutes results in an increased incidence of nausea and vomiting.

Management of overdose

GATICIL IV is not removed in significant quantities by haemodialysis.