Tygacil · 4.6 Fertility, pregnancy and lactation · 1

HOS-094236 · has-adverse-reaction-information · PDF-Seite 7

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 Very Common Uncommon Rare Frequency Organ Class Common ≥ 1/100 to ≥ 1/1,000 to ≥ 1/10,000 to not known ≥ 1/10 < 1/10 < 1/100 < 1/1,000 (cannot be estimated from the available data) Infections and sepsis/septic infestations shock, pneumonia, abscess, infections Blood and prolonged thrombocytop hypofibrinoge lymphatic activated enia, naemia system partial increased disorders thromboplasti international n time normalised (aPTT), ratio (INR) prolonged prothrombin time (PT) Immune anaphylaxis/ system anaphylactoid disorders reactions* (see sections

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HOS-094232 · has-contraindication-information · PDF-Seite 3

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.

HOS-094231 · has-indication-information · PDF-Seite 2

Tygacil 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). Tygacil 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.

HOS-094234 · has-interaction-information · PDF-Seite 5

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 5 (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).

HOS-094235 · has-pregnancy-information · PDF-Seite 6

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).

HOS-094233 · has-warning-information · PDF-Seite 3

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). 3 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,

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