Oritavancin

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). 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.

Very limited data are available in patients with severe renal impairment. Renal impairment had no clinically relevant effect on the exposure of oritavancin, however caution should be exercised when prescribing oritavancin in patients with severe renal impairment. Oritavancin is not removed from blood by haemodialysis procedures.

The pharmacokinetics of oritavancin in patients with severe hepatic impairment (Child-Pugh Class C) has not been evaluated, however based on pharmacokinetic parameters, severe hepatic impairment is not expected to have an impact on oritavancin exposure. Therefore no dose adjustment is required, even if caution should be exercised when prescribing oritavancin to patients with severe hepatic impariment (Child-Pugh Class C).

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.

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. 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 wcoagulation testith 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.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of oritavancin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of oritavancin during pregnancy unless the clinical condition of the woman requires treatment with oritavancin.

Available pharmacodynamic/toxicological data in animals have shown excretion of oritavancin in milk. 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 breastfeeding 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 are 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.

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.

Frequency of adverse reactions by system organ class:

^* These reactions may be infusion-related
^** Infusion site reactions includes: infusion site phlebitis, infusion site erythema, extravasation, induration, pruritus, rash, oedema peripheral.