Tigecycline 50 Mg Infusion

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

• Complicated skin and skin structure infections, (excluding diabetic foot 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 TIGECYCLINE PFIZER is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of TIGECYCLINE PFIZER should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment with TIGECYCLINE PFIZER 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

Use in patients with renal impairment

No dosage adjustment of TIGECYCLINE PFIZER is necessary in patients with renal impairment or in patients undergoing haemodialysis (see section 5.2, Pharmacokinetic properties, Special populations, 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 PFIZER in patients with severe hepatic impairment (Child Pugh C), the dose of TIGECYCLINE PFIZER 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, Pharmacokinetic properties, Special populations, Hepatic insufficiency).

Elderly population

No dosage adjustment is necessary in elderly patients (see section 4.4, Use in the elderly).

Paediatric population

Clinical trials to establish the safety and effectiveness of TIGECYCLINE PFIZER in patients under 18 years of age have not been conducted. Therefore, use in patients under 18 years of age is not recommended (see section 4.4).

Method of administration

Intravenous infusion.

TIGECYCLINE PFIZER is contraindicated for use:

• in patients who have known hypersensitivity to tigecycline or to any of the excipients of TIGECYCLINE PFIZER (listed in section 6.1)
• Pregnancy and lactation

An increase in all-cause mortality has been observed across Phase 3 and 4 clinical trials in TIGECYCLINE PFIZER treated patients versus comparator-treated patients. In a pooled analysis of 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TIGECYCLINE PFIZER and 3.0% (110/3646) of patients receiving comparator medicines resulting in an unadjusted risk difference of 0.9% (95% CI 0.1; 1.8). In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1; 1.2) between TIGECYCLINE PFIZER and comparator-treated patients. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options.

TIGECYCLINE PFIZER should not be used in hospital associated pneumonia (HAP) or ventilator associated pneumonia (VAP). The safety and efficacy of TIGECYCLINE PFIZER in patients with hospital acquired pneumonia (HAP) have not been established. In a study of patients with hospital acquired pneumonia, patients were randomised to receive TIGECYCLINE PFIZER (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 (VAP) who received TIGECYCLINE PFIZER had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and higher mortality (25/131 [19.1%] versus 15/122 [12.3%]) than the comparator. Of those patients with ventilator-associated pneumonia and bacteraemia at baseline, those who received TIGECYCLINE PFIZER had greater mortality (9/18 [50.0%] versus 1/13 [7.7%]) than the comparator.

Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial medicines, including TIGECYCLINE PFIZER, and may be life-threatening. TIGECYCLINE PFIZER is structurally similar to tetracycline class antibiotics. Therefore, TIGECYCLINE PFIZER should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics.

Results of studies in rats with TIGECYCLINE PFIZER have shown bone discolouration. TIGECYCLINE PFIZER may be associated with permanent tooth discolouration in humans during tooth development. Pseudomembranous colitis has been reported with TIGECYCLINE PFIZER. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of TIGECYCLINE PFIZER.

Caution should be exercised when considering TIGECYCLINE PFIZER monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In Phase 3 and 4 cIAI studies (n=2775), 140/1382 TIGECYCLINE PFIZER-treated patients and 142/1393 comparator-treated patients presented with intestinal perforations. Of these patients, 8/140 patients treated with TIGECYCLINE PFIZER and 8/142 patients treated with comparator developed sepsis/septic shock. The relationship of this outcome to treatment cannot be established.

Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with TIGECYCLINE PFIZER. TIGECYCLINE PFIZER is structurally similar to tetracycline class antibiotics and may have similar adverse effects. Such effects may include photosensitivity, pseudotumour cerebri, and anti-anabolic action (which has led to increased BUN, uraemia, acidosis, and hyperphosphataemia). Pancreatitis has been reported with the use of TIGECYCLINE PFIZER. Acute pancreatitis, which can be fatal, has occurred in association with TIGECYCLINE PFIZER treatment. The diagnosis of acute pancreatitis should be considered in patients taking TIGECYCLINE PFIZER who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improved after TIGECYCLINE PFIZER discontinuation. Cessation of the treatment with TIGECYCLINE PFIZER in cases suspected of having developed pancreatitis is advised.

Coagulopathy

TIGECYCLINE PFIZER may prolong both prothrombin time (PT) and activated partial thromboplastin time (aPTT). Additionally, hypofibrinogenaemia has been reported with the use of TIGECYCLINE PFIZER. Therefore, blood coagulation parameters such as PT or other suitable anticoagulation test, including blood fibrinogen, should be monitored prior to treatment initiation with TIGECYCLINE PFIZER and regularly while on treatment. Special care is recommended in seriously ill patients and in patients also using anticoagulants (see section 4.5).

Use of TIGECYCLINE PFIZER may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection, including clostridium difficile colitis occurs, appropriate measures should be taken.

Paediatric use

Clinical trials to establish the safety and effectiveness of TIGECYCLINE PFIZER in patients under 18 years of age have not been conducted. Therefore, use in patients under 18 years of age is not recommended.

Use in the elderly

In a pooled analysis of 3900 subjects who received TIGECYCLINE PFIZER in Phase 3 and 4 clinical studies, 1026 were 65 years and over. Of these 419 were 75 years and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects. No dosage adjustment is necessary in elderly patients.

Excipient information

This medicine contains less than 1 mmol sodium (23 mg) per 5 mL of suspension, that is to say essentially u2018sodium-freeu2019.

TIGECYCLINE PFIZER (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 drug interaction study. TIGECYCLINE PFIZER 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 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 TIGECYCLINE PFIZER. Therefore, no dosage adjustment is necessary when TIGECYCLINE PFIZER is administered with digoxin.

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

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

In vitro studies using Caco-2 cells indicate that TIGECYCLINE PFIZER does not inhibit digoxin flux, suggesting that TIGECYCLINE PFIZER is not a P-glycoprotein (P-gp) inhibitor. This in vitro information is consistent with the lack of effect of TIGECYCLINE PFIZER on digoxin clearance noted in the in vivo drug interaction study described above. TIGECYCLINE PFIZER 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 PFIZER is not known. Coadministration of P-gp inhibitors (e.g., ketoconazole or ciclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of TIGECYCLINE PFIZER.

Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective. Concomitant use of TIGECYCLINE PFIZER and calcineurin inhibitors such as tacrolimus or ciclosporin 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 PFIZER to avoid medicine toxicity.

Interference with laboratory and other diagnostic tests

There are no reported drug-laboratory test interactions.

Pregnancy

TIGECYCLINE PFIZER may cause foetal harm when administered to a pregnant woman. Results of animal studies indicate that TIGECYCLINE PFIZER crosses the placenta and is found in foetal tissues. There are no adequate and well-controlled studies of TIGECYCLINE PFIZER in pregnant women. TIGECYCLINE PFIZER should not be used during pregnancy.

Breastfeeding

Results from animal studies using 14C-labeled TIGECYCLINE PFIZER indicate that TIGECYCLINE PFIZER is excreted readily via the milk of lactating rats. It is not known whether this medicine is excreted in human milk. Therefore, TIGECYCLINE PFIZER should not be used during breastfeeding.

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

Tabulated summary of adverse reactions

Expected frequency of adverse reactions is presented in CIOMS frequency categories: Very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000).

For patients who received TIGECYCLINE PFIZER, the following adverse reactions were reported:

* AST and ALT abnormalities in TIGECYCLINE PFIZER 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 a pooled analysis of all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TIGECYCLINE PFIZER and 3.0% (110/3646) of subjects receiving comparator medicines. In a pooled analysis of these trials, the risk difference of all-cause mortality was 0.9% (95% CI 0.1; 1.8) between TIGECYCLINE PFIZER and comparator-treated subjects. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1; 1.2) between TIGECYCLINE PFIZER-treated and comparator-treated subjects. No significant differences were observed between TIGECYCLINE PFIZER and comparators within each infection type. The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, or complications of infection or underlying co-morbidities. The most common treatment-emergent adverse reactions, in patients treated with TIGECYCLINE PFIZER were nausea 29.9% [19.3% mild; 9.2% moderate; 1.4% severe] and vomiting 19.9% [12.1% mild; 6.8% moderate; 1.1% severe]. In general, nausea or vomiting occurred early (days 1 - 2). Discontinuation from TIGECYCLINE PFIZER was most frequently associated with nausea (1.6%) and vomiting (1.3%).

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 u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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