TENKASI Powder for solution for infusion Ref.[50255] Active ingredients: Oritavancin

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock have been reported with the use of oritavancin. If an acute hypersensitivity reaction occurs during oritavancin infusion, oritavancin should be discontinued immediately and appropriate supportive care should be instituted.

No data are available on cross-reactivity between oritavancin and other glycopeptides, including vancomycin. Before using oritavancin it is important to inquire carefully about previous hypersensitivity reactions to glycopeptides (e.g. vancomycin, telavancin). Due to the possibility of cross-hypersensitivity, there should be careful monitoring of patients with any history of glycopeptide hypersensitivity during and after the infusion.

Infusion related reactions

Oritavancin is given via intravenous infusion over 3 hours to minimise the risk of infusion related reactions. Intravenous infusions of oritavancin can cause reactions that resemble “red man syndrome”, including flushing of the upper body, urticaria, pruritis and/or rash. Infusion-associated reactions characterized by chest pain, chest discomfort, chills, tremor, back pain, neck pain, dyspnoea, hypoxia, abdominal pain and fever have been observed with the use of oritavancin, including after the administration of more than one dose of oritavancin (1200mg) during a single course of therapy. If reactions do occur, stopping or slowing the infusion may result in cessation of these symptoms (see section 4.8).

Need for additional antibacterial agents

Oritavancin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, oritavancin should be coadministered with appropriate antibacterial agent(s).

Concomitant use of warfarin

Oritavancin has been shown to artificially prolong prothrombin time (PT) and international normalised ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an oritavancin dose.

Interference with assay for coagulation tests

Oritavancin has been shown to interfere with certain laboratory coagulation tests (see sections 4.3 and 4.5). Oritavancin concentrations that are found in the blood of patients following administration of a single dose have been shown to artificially prolong:

• aPTT for up to 120 hours,
• PT and INR for up to 12 hours,
• Activated Clotting Time (ACT) for up to 24 hours,
• Silica Clot Time (SCT) for up to 18 hours, and
• Dilute Russell’s Viper Venom Test (DRVVT) for up to 72 hours.

These effects result from oritavancin binding to and preventing the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. For patients who require aPTT monitoring within 120 hours of oritavancin dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.

The Chromogenic Factor Xa Assay, the Thrombin Time (TT) assay and the assays used for the diagnosis of Heparin Induced Thrombocytopenia (HIT) are not affected by oritavancin. In vitro, oritavancin 46.6 μg/mL did not affect an assay for activated protein C resistance (APCR), suggesting that there is a low likelihood that oritavancin will interfere with this test. However, APCR is a phospholipid-based test and it cannot be ruled out that higher concentrations of oritavancin that may occur during clinical use could interfere with this test.

No effect of oritavancin on the in vivo coagulation system was observed in nonclinical and clinical studies.

Clostridioides difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported for oritavancin and may range in severity from mild to life threatening diarrhoea. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of oritavancin (see section 4.8). In such a circumstance, the use of supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered.

Superinfection

The use of antibacterial medicinal products may increase the risk of overgrowth of non-susceptible micro-organisms. If superinfection occurs, appropriate measures should be taken.

Osteomyelitis

In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the oritavancin-treated arm than in the vancomycin-treated arm (see section 4.8). Patients should be monitored for signs and symptoms of osteomyelitis after administration of oritavancin. If osteomyelitis is suspected or diagnosed, appropriate alternative antibacterial therapy should be instituted.

Abscess

In the Phase 3 clinical trials, slightly more cases of newly emergent abscesses were reported in the oritavancin-treated arm than in the vancomycin-treated arm (4.6% vs 3.4%, respectively) (see section 4.8). If newly emergent abscesses occur, appropriate measures should be taken.

Limitations of the clinical data

In the two major trials in ABSSSI the types of infections treated were confined to cellulitis, abscesses and wound infections only. Other types of infections have not been studied. There is limited experience in clinical studies in patients with bacteraemia, peripheral vascular disease or neutropenia, in immunocompromised patients, in patients aged >65 years and in infections due to S. pyogenes.

Substances metabolised by cytochrome P450

A screening drug-drug interaction study was conducted in healthy volunteers (n=16) evaluating the concomitant administration of a single 1,200 mg dose of oritavancin with probe substrates for several CYP450 enzymes. Oritavancin was found to be a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or a weak inducer (CYP3A4 and CYP2D6) of several CYP isoforms.

Caution should be used when administering oritavancin concomitantly with medicinal products with a narrow therapeutic window that are predominantly metabolised by one of the affected CYP450 enzymes(e.g., warfarin), as co-administration may increase (e.g., for CYP2C9 substrates) or decrease (e.g., for CYP2D6 substrates) concentrations of the narrow therapeutic range medicinal product. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given oritavancin while on a potentially affected compound (e.g. patients should be monitored for bleeding, if concomitantly receiving oritavancin and warfarin) (see section 4.4). A study to assess the drug-drug interaction effect of a single 1,200mg dose of oritavancin on the pharmacokinetics of S-warfarin following a single dose was conducted in 36 healthy subjects. S-warfarin pharmacokinetics were evaluated following a single dose of warfarin 25 mg given alone, or administered at the start, 24, or 72 hours after a single 1,200mg dose of oritavancin. The results showed no effect of oritavancin on Swarfarin AUC and C_max.

Drug-laboratory test interactions (see sections 4.3 and 4.4)

Oritavancin binds to and prevents the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. Oritavancin concentrations achieved in the blood after 1,200 mg doses may produce falsely elevated results from certain laboratory tests (see Table 1).

Table 1. Coagulation tests affected by oritavancin:

Pregnancy

There are no or limited amount of data from the use of oritavancin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of oritavancin during pregnancy unless the potential benefit justifies the potential risk to the foetus.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of oritavancin in milk (see section 5.3). It is unknown whether oritavancin/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from oritavancin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies have revealed no evidence of impaired fertility due to oritavancin at the highest concentrations administered, however, there is no data on the effects of oritavancin on human fertility.

Oritavancin has a minor influence on the ability to drive and use machines. Dizziness may occur and this may have an effect on driving and use of machines (see section 4.8).

Summary of the safety profile

The most commonly reported adverse reactions (≥5%) were: nausea, hypersensitivity reactions, infusion site reactions, and headache. The most commonly reported serious adverse reaction was cellulitis (1.1%). The most common reported reasons for discontinuation were cellulitis (0.4%) and osteomyelitis (0.3%). Female patients had a higher reporting rate for adverse reactions than male patients.

Tabulated list of adverse reactions

Adverse reactions for oritavancin from the pooled Phase 3 ABSSSI clinical trials with single dose oritavancin are listed by system organ class in the following table.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2. Frequency of adverse reactions by system organ class:

^* These reactions may be infusion-related (see section 4.4)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Sodium chloride solution should not be used for dilution as it is incompatible with oritavancin and may cause precipitation of the medicinal product. Therefore, other substances, additives or other medicinal products mixed in sodium chloride solution for intravenous use should not be added to oritavancin single-use vials or infused simultaneously through the same intravenous line or through a common intravenous port. In addition, medicinal products formulated at a basic or neutral pH may be incompatible with oritavancin (see section 6.6).