Orbactiv

Contraindications

Hypersensitivity

Use of intravenous unfractionated heparin sodium within 120 hr (5 days) of oritavancin administration

Cautions

Please refer to the patient counseling section of the prescribing information

Shown to artificially prolong PT/INR for up to 12 hr (5.1); coadministration with warfarin may result in higher exposure of warfarin and increase risk for bleeding; monitor frequently for signs of bleeding

shown to artificially prolong aPTT for up to 120 hours, and may prolong PT and INR for up to 12 hr and ACT for up to 24 hr; for patients who require aPTT monitoring within 120 hr of dosing, consider a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT

Hypersensitivity reported, including possible cross-sensitivity to other glycopeptides (eg, dalbavancin, telavancin, vancomycin); discontinue infusion if signs of acute hypersensitivity occur; monitor closely patients with known hypersensitivity to glycopeptides

Infusion-related reactions reported, including pruritus, urticaria, and/or flushing; consider slowing infusion rate or interrupting infusion

Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs and may range from mild diarrhea to fatal colitis; evaluate patients if diarrhea occurs

In clinical trials, more cases of osteomyelitis were reported with oritavancin compared with vancomycin; if osteomyelitis suspected, institute appropriate alternate antibacterial therapy

To reduce development of drug-resistant bacteria and maintain effectiveness, use only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria

Coagulation test interference

• Artificially prolongs aPTT for up to 120 hr, and may prolong PT and INR for up to 12 hr and ACT for up to 24 hr
• For patients who require aPTT monitoring within 120 hr of dosing, consider a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT
• Effects on activated clotting time (ACT) are expected since the phospholipid reagents are also used in this coagulation test
• Oritavancin has no effect on the coagulation system

For at least 120 hours (5 days) after receiving oritavancin, avoid using heparin.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop using oritavancin and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

Other drugs may interact with oritavancin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take warfarin (Coumadin).

This is not a complete list of Orbactiv drug interactions. Ask your doctor or pharmacist for more information.

Oritavancin is an antibiotic that fights bacteria.

Oritavancin is used to treat severe skin infections caused by bacteria.

Oritavancin may also be used for purposes not listed in this medication guide.

Oritavancin is injected into a vein through an IV, and is usually given only one time in a single dose. A healthcare provider will give you this injection.

Oritavancin must be given slowly, and the IV infusion can take at least 3 hours to complete.

This medicine can cause unusual results with certain medical tests for up to 120 hours (5 days) after your injection. Tell any doctor who treats you that you have been treated with oritavancin.

Call your doctor promptly if your symptoms do not improve after receiving oritavancin.

Weak inhibitor of CYP2C9 and 2C19; weak inducer of 3A4 and 2D6.1

Not a substrate or inhibitor of the P-glycoprotein (P-gp) efflux transporter.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

If used concomitantly with drugs that are metabolized by CYP2C9, 2C19, 3A4, or 2D6 and have a narrow therapeutic index, use caution and closely monitor for signs of toxicity or lack of efficacy.1

Specific Drugs and Laboratory Tests

• Semisynthetic lipoglycopeptide antibacterial derived from chloroeremomycin, a naturally occurring glycopeptide.1 7 8 Structurally similar to vancomycin, but has side chains that enhance antibacterial activity.7 8

• Mechanism of action similar to that of other glycopeptides (e.g., dalbavancin, telavancin, vancomycin).7 Binds to d-alanyl-d-alanine terminus of growing peptidoglycan chains, thereby inhibiting bacterial cell wall synthesis;1 4 7 8 binds to peptide bridging segments of the cell wall, thereby inhibiting transpeptidation (crosslinking) step of cell wall biosynthesis; dimerizes and anchors into bacterial cell membrane, which improves binding to target.1 4 7 8 10 11

• Bactericidal in vitro against certain gram-positive bacteria, including staphylococci, streptococci, and enterococci.1 7 8 10 13

• Active in vitro and in clinical studies against S. aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]),1 4 5 6 13 20 24 S. pyogenes (group A β-hemolytic streptococci, GAS),1 4 5 6 21 S. agalactiae (group B streptococci, GBS),1 4 5 6 S. dysgalactiae,1 5 6 S. anginosus group (includes S. anginosus, S. intermedius, and S. constellatus),1 5 6 and vancomycin-susceptible E. faecalis.1 4 5 6 13

• Active in vitro against vancomycin-susceptible E. faecium,1 4 Clostridium perfringens,4 C. difficile,4 22 23 Peptostreptococcus,4 Propionibacterium acnes,4 S. pneumoniae,18 vancomycin-intermediate S. aureus (VISA),24 vancomycin-resistant S. aureus (VRSA),18 and daptomycin-nonsusceptible S. aureus (DNSSA).24 However, safety and efficacy in treating clinical infections due to these bacteria not established.1

• Reduced susceptibility or resistance to oritavancin produced in vitro by serial passage of S. aureus and E. faecalis in the presence of increasing concentrations of the drug.1

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Changes in skin color
• dry, red, hot, or irritated skin
• fast, pounding, or irregular heartbeat or pulse
• pain, swelling, or tenderness in the skin

• Black, tarry stools
• blistering, peeling, or loosening of the skin
• fever
• hives, itching skin, or rash
• increase in bone pain
• joint pain, stiffness, or swelling
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• redness, soreness, or itching skin
• sores, welting, or blisters
• swelling of the eyelids, face, lips, hands, or feet
• swollen glands
• tightness in the chest
• unusual bleeding or bruising

• Abdominal or stomach tenderness
• severe abdominal or stomach cramps and pain
• watery and severe diarrhea, which may also be bloody

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Dizziness
• headache
• nausea or vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

4.1 Intravenous Unfractionated Heparin Sodium

Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after Orbactiv administration because the activated partial thromboplastin time (aPTT) test results may remain falsely elevated for up to 120 hours (5 days) after Orbactiv administration [see Warnings and Precautions (5.1) and Drug Interactions (7.2)].

Hypersensitivity

Orbactiv is contraindicated in patients with known hypersensitivity to Orbactiv.

Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

A total of 1987 adults with clinically documented ABSSSI suspected or proven to be due to Gram-positive pathogens were randomized into two identically designed, randomized, double-blind, multi-center, multinational, non-inferiority trials (Trial 1 and Trial 2) comparing a single 1200 mg intravenous dose of Orbactiv to intravenous vancomycin (1 g or 15 mg/kg every 12 hours) for 7 to 10 days. The primary analysis population (modified intent to treat, mITT) included all randomized patients who received any study drug. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. Patient demographic and baseline characteristics were balanced between treatment groups. Approximately 64% of patients were Caucasian and 65% were males. The mean age was 45 years and the mean body mass index was 27 kg/m2. Across both trials, approximately 60% of patients were enrolled from the United States and 27% of patients from Asia. A history of diabetes was present in 14% of patients. The types of ABSSSI across both trials included cellulitis/erysipelas (40%), wound infection (29%), and major cutaneous abscesses (31%). Median infection area at baseline across both trials was 266.6 cm2.

The primary endpoint in both trials was early clinical response (responder), defined as cessation of spread or reduction in size of baseline lesion, absence of fever, and no rescue antibacterial drug at 48 to 72 hours after initiation of therapy.

Table 6 provides the efficacy results for the primary endpoint in Trial 1 and Trial 2 in the primary analysis population.

A key secondary endpoint in these two ABSSSI trials evaluated the percentage of patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy. Table 7 summarizes the findings for this endpoint in the two ABSSSI trials.

Another secondary efficacy endpoint in the two trials was investigator-assessed clinical success at post therapy evaluation at Day 14 to 24 (7 to 14 days from end of blinded therapy). A patient was categorized as a clinical success if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms related to primary ABSSSI site (erythema, induration/edema, purulent drainage, fluctuance, pain, tenderness, local increase in heat/warmth) such that no further treatment with antibacterial drugs was needed.

Table 8 summarizes the findings for this endpoint in the mITT and clinically evaluable population in these two ABSSSI trials. Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the post therapy visits. Therefore, comparisons of Orbactiv to vancomycin based on clinical success rates at these visits cannot be utilized to establish non-inferiority conclusions.

Outcomes by Baseline Pathogen: Table 9 shows outcomes in patients with an identified baseline pathogen in the microbiological Intent-to-Treat (microITT) population in a pooled analysis of Trial 1 and Trial 2. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up study day 14 to 24.

Caution is recommended. Excretion into human milk: Unknown Excretion into animal milk: Yes