1.1 Acute Bacterial Skin and Skin Structure Infections

ORBACTIV™ (Oritavancin) for injection is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms:

Staphylococcus aureus (including methicillin-susceptible and methicillin–resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only).

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ORBACTIV and other antibacterial drugs, ORBACTIV should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2.1 Recommended Dosage

The recommended dosing for ORBACTIV is a single 1200 mg dose administered by intravenous infusion over 3 hours in patients 18 years and older.

2.2 Preparation of ORBACTIV for Intravenous Infusion

ORBACTIV is intended for intravenous infusion, only after reconstitution and dilution.

Three ORBACTIV 400 mg vials need to be reconstituted and diluted to prepare a single 1200 mg intravenous dose.

Reconstitution: Aseptic technique should be used to reconstitute three ORBACTIV 400 mg vials.
 

• Add 40 mL of sterile water for injection (WFI) to reconstitute each vial to provide a 10 mg/mL solution per vial.
• For each vial, gently swirl to avoid foaming and ensure that all ORBACTIV powder is completely reconstituted in solution.
• Each vial should be inspected visually for particulate matter after reconstitution and should appear to be clear, colorless to pale yellow solution.

Dilution: Use ONLY 5% dextrose in sterile water (D5W) for dilution. Do NOT use Normal Saline for dilution as it is incompatible with ORBACTIV and may cause precipitation of the drug. Use aseptic technique to:
 

• Withdraw and discard 120 mL from a 1000 mL intravenous bag of D5W.
• Withdraw 40 mL from each of the three reconstituted vials and add to D5W intravenous bag to bring the bag volume to 1000 mL. This yields a concentration of 1.2 mg/mL.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparing the final intravenous solution.

Diluted intravenous solution in an infusion bag should be used within 6 hours when stored at room temperature, or used within 12 hours when refrigerated at 2 to 8°C (36 to 46°F). The combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 3 hour infusion time should not exceed 6 hours at room temperature or 12 hours if refrigerated.

2.3 Incompatibilities

ORBACTIV is administered intravenously. ORBACTIV should only be diluted in D5W. Do NOT use normal saline for dilution as it is incompatible with ORBACTIV and may cause precipitation of the drug. Therefore other intravenous substances, additives or other medications mixed in normal saline should not be added to ORBACTIV single-use vials or infused simultaneously through the same IV line or through a common intravenous port. In addition, drugs formulated at a basic or neutral pH may be incompatible with ORBACTIV. ORBACTIV should not be administered simultaneously with commonly used intravenous drugs through a common intravenous port. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of ORBACTIV with D5W.

4.1 Intravenous Unfractionated Heparin Sodium

Use of intravenous unfractionated heparin sodium is contraindicated for 48 hours after ORBACTIV administration because the activated partial thromboplastin time (aPTT) test results are expected to remain falsely elevated for approximately 48 hours after ORBACTIV administration [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]

4.2 Hypersensitivity

ORBACTIV is contraindicated in patients with known hypersensitivity to ORBACTIV.

5.1 Potential Risk of Bleeding with Concomitant Use of Warfarin

Co-administration of ORBACTIV and warfarin may result in higher exposure of warfarin, which may increase the risk of bleeding. Use ORBACTIV in patients on chronic warfarin therapy only when the benefits can be expected to outweigh the risk of bleeding. Frequently monitor for signs of bleeding. [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

ORBACTIV has been shown to artificially prolong PT and INR for up to 24 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 24 hours after an ORBACTIV dose. [see Warnings and Precautions (5.2)]

5.2 Coagulation Test Interference

ORBACTIV has been shown to artificially prolong aPTT for 48 hours and the PT and INR for 24 hours by binding to and preventing action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests.

For patients who require aPTT monitoring within 48 hours of ORBACTIV 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.

Effects by ORBACTIV on activated clotting time (ACT) are expected since the phospholipid reagents are also utilized in this coagulation test. ORBACTIV has no effect on the coagulation system. [see Contraindications (4.1) and Drug Interactions (7.2)]

5.3 Hypersensitivity

Serious hypersensitivity reactions have been reported with the use of ORBACTIV. If an acute hypersensitivity reaction occurs during ORBACTIV infusion, discontinue ORBACTIV immediately and institute appropriate supportive care. Before using ORBACTIV, inquire carefully about previous hypersensitivity reactions to glycopeptides. Due to the possibility of cross-sensitivity, carefully monitor for signs of hypersensitivity during ORBACTIV infusion in patients with a history of glycopeptide allergy. In the Phase 3 ABSSSI clinical trials, the median onset of hypersensitivity reactions in ORBACTIV-treated patients was 1.2 days and the median duration of these reactions was 2.4 days. [see Adverse Reactions (6.1)]

5.4 Infusion Related Reactions

Infusion related reactions have been reported with ORBACTIV including pruritus, urticaria or flushing. If reactions do occur, consider slowing or interrupting ORBACTIV infusion. [see Adverse Reactions (6.1)]

5.5 Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including ORBACTIV, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical eva luation should be instituted as clinically indicated.

5.6 Osteomyelitis

In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the ORBACTIV treated arm than in the vancomycin-treated arm. Monitor patients for signs and symptoms of osteomyelitis. If osteomyelitis is suspected or diagnosed, institute appropriate alternate antibacterial therapy [see Adverse Reactions (6.1)].

5.7 Development of Drug Resistant Bacteria

Prescribing ORBACTIV in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Patient Counseling Information (17)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of ORBACTIV cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ORBACTIV has been eva luated in two, double-blind, controlled ABSSSI clinical trials, which included 976 adult patients treated with a single 1200 mg intravenous dose of ORBACTIV and 983 patients treated with intravenous vancomycin for 7 to 10 days. The median age of patients treated with ORBACTIV was 45.6 years, ranging between 18 and 89 years of age with 8.8% ≥65 years of age. Patients treated with ORBACTIV were predominantly male (65.4%), 64.4% were Caucasian, 5.8% were African American, and 28.1% were Asian. Safety was eva luated for up to 60 days after dosing.

In the pooled ABSSSI clinical trials, serious adverse reactions were reported in 57/976 (5.8%) patients treated with ORBACTIV and 58/983 (5.9%) treated with vancomycin. The most commonly reported serious adverse reaction was cellulitis in both treatment groups: 11/976 (1.1%) in ORBACTIV and 12/983 (1.2%) in the vancomycin arms, respectively.

The most commonly reported adverse reactions (≥3%) in patients receiving a single 1200 mg dose of ORBACTIV in the pooled ABSSSI clinical trials were: headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea.

In the pooled ABSSSI clinical trials, ORBACTIV was discontinued due to adverse reactions in 36/976 (3.7%) of patients; the most common reported reactions leading to discontinuation were cellulitis (4/976, 0.4%) and osteomyelitis (3/976, 0.3%).

Table 1 provides selected adverse reactions occurring in ≥ 1.5% of patients receiving ORBACTIV in the pooled ABSSSI clinical trials. There were 540 (55.3%) patients in the ORBACTIV arm and 559 (56.9%) patients in the vancomycin arm, who reported ≥1 adverse reaction.

The following selected adverse reactions were reported in ORBACTIV-treated patients at a rate of less than 1.5%:

Blood and lymphatic system disorders: anemia, eosinophilia

General Disorders and administration site conditions: infusion site erythema, extravasation, induration, pruritis, rash, edema peripheral

Immune system disorders: hypersensitivity

Infections and infestations: osteomyelitis

Investigations: total bilirubin increased, hyperuricemia

Metabolism and nutrition disorders: hypoglycemia

Musculoskeletal and connective tissue disorders: tenosynovitis, myalgia

Respiratory, thoracic and mediastinal disorders: bronchospasm, wheezing

Skin and Subcutaneous Tissue Disorders: urticaria, angioedema, erythema multiforme, pruritis, leucocytoclastic vasculitis, rash.