1.1 Acute Bacterial Skin and Skin Structure Infections

ORBACTIV® (oritavancin) 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 or prevent 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 Dosage and Administration Overview

There are two oritavancin products (ORBACTIV and KIMYRSA™, another oritavancin product) that:

• Are supplied in different dose strengths of oritavancin [see Dosage Forms and Strengths (3)].
• Have different recommended durations of infusion [see Dosage and Administration (2.2)].
• Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents [see Dosage and Administration (2.3, 2.4)].

Carefully follow the recommended dosage and dose preparation instructions for ORBACTIV in this prescribing information (PI) [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)]. Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.

2.2 Recommended Dosage

The recommended dosage of ORBACTIV is 1,200 mg administered as a single dose by intravenous infusion over 3 hours in patients 18 years and older [see Warnings and Precautions (5.3)].

2.3 Preparation of ORBACTIV for Intravenous Infusion

There are two oritavancin products (ORBACTIV and KIMYRSA, another oritavancin product) that have differences in dose strengths, duration of infusion, reconstitution and dilution instructions, and compatible diluents. Carefully follow the reconstitution, and dilution instructions with the appropriate compatible diluent for ORBACTIV specified in this prescribing information. Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.

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 1,200 mg intravenous dose.

2.4 Compatibility

ORBACTIV solution for administration by 3-hour infusion is ONLY compatible with:

• 5% dextrose injection (D5W)

2.5 Incompatibilities

ORBACTIV is administered intravenously. ORBACTIV should only be diluted in D5W. Do NOT use sodium chloride injection 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 sodium chloride injection should not be added to ORBACTIV single-dose 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 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)].

4.2 Hypersensitivity

ORBACTIV is contraindicated in patients with known hypersensitivity to oritavancin products.

5.1 Coagulation Test Interference

ORBACTIV has been shown to artificially prolong aPTT for up to 120 hours, PT and INR for up to 12 hours, and activated clotting time (ACT) for up to 24 hours following administration of a single 1,200 mg dose by binding to and preventing action of the phospholipid reagents commonly used in laboratory coagulation tests. ORBACTIV has also been shown to elevate D-dimer concentrations up to 72 hours after ORBACTIV administration.

For patients who require aPTT monitoring within 120 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 [see Contraindications (4.1) and Drug Interactions (7.2)].

ORBACTIV has no effect on the coagulation system in vivo.

5.2 Hypersensitivity

Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of oritavancin products, including 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)].

5.3 Infusion Related Reactions

ORBACTIV is administered as a single dose by intravenous infusion, using a total infusion time of 3 hours to minimize the risk of infusion-related reactions. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including oritavancin products (e.g. ORBACTIV), including flushing of the upper body, urticaria, pruritus and/or rash [see Adverse Reactions (6.1)]. Infusion reactions characterized by chest pain, back pain, chills and tremor have been observed with the use of ORBACTIV, including after the administration of more than one dose of ORBACTIV during a single course of therapy.

Stopping or slowing the infusion may result in cessation of these reactions. The safety and effectiveness of more than one dose of ORBACTIV during a single course of therapy have not been established [see Dosage and Administration (2.2)].

5.4 Clostridioides difficile-associated Diarrhea

Clostridioides 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 evaluation should be instituted as clinically indicated.

5.5 Potential Risk of Bleeding with Concomitant Use of Warfarin

ORBACTIV has been shown to artificially prolong prothrombin time (PT) and international normalized ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an ORBACTIV dose [see Warnings and Precautions (5.1)].

Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin [see Drug Interactions (7.1)].

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 or a prophylactic indication 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 evaluated in two, double-blind, controlled ABSSSI clinical trials, which included 976 adult patients treated with a single 1,200 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 evaluated 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 1,200 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, pruritus, 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, pruritus, leucocytoclastic vasculitis, rash

6.2 Immunogenicity

There is potential for immunogenicity following administration of oritavancin products, including ORBACTIV. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Because several factors in an assay may influence the observed incidence of antibody positivity, comparison of the incidence of antibodies to oritavancin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Positive indirect and direct antiglobulin tests (IAT/DAT) were noted with the administration of ORBACTIV and KIMYRSA (hereinafter referred to as another oritavancin product) in studies with healthy subjects and patients with ABSSSI. In a randomized, open-label, multi-center ABSSSI study, positive antiglobulin tests were reported in 9.6% (5/52) of subjects who received ORBACTIV and 2% (1/50) of subjects who received another oritavancin product. Oritavancin-dependent RBC antibodies were detected when tested in the presence of drug for three subjects in the ORBACTIV group.

In a multiple dose study with ORBACTIV in healthy volunteers, 90% (9/10) of subjects had a positive IAT 14 days after the second infusion.

In a healthy volunteer study, 66% (22/32) of subjects receiving another oritavancin product had a positive IAT 15 days after receiving dosing and one subject had a positive DAT at 8 days after dosing.

There were no reports of hemolysis in subjects who had positive IAT/DAT. If hemolytic anemia develops following treatment with ORBACTIV provide appropriate care. Positive IAT may interfere with cross-matching before blood transfusion [see Drug Interactions (7.2)].

7.1 Effect of ORBACTIV on CYP Substrates

A screening drug-drug interaction study indicated that ORBACTIV is a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms [see Clinical Pharmacology (12.3)]. A drug-drug interaction study that assessed the interaction potential of a single 1,200 mg dose of ORBACTIV on the pharmacokinetics of S-warfarin (CYP2C9 probe substrate) showed no effect of ORBACTIV on S-warfarin Cmax or AUC.

Avoid administering ORBACTIV concomitantly with drugs that are predominantly metabolized by one of the affected CYP450 enzymes, as co-administration may increase or decrease concentrations of those drugs. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given ORBACTIV while on a potentially affected compound (e.g. patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin).

7.2 Drug-Laboratory Test Interactions

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of ORBACTIV in pediatric patients (younger than 18 years of age) have not been established.

8.5 Geriatric Use

The pooled Phase 3 ABSSSI clinical trials of ORBACTIV did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

No dosage adjustment of ORBACTIV is needed in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3)]. The pharmacokinetics of ORBACTIV in severe renal impairment have not been evaluated. ORBACTIV is not removed from blood by hemodialysis.

8.7 Hepatic Impairment

No dosage adjustment of ORBACTIV is needed in patients with mild or moderate hepatic impairment. The pharmacokinetics of ORBACTIV in patients with severe hepatic insufficiency has not been studied [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Oritavancin is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

The antimicrobial activity of oritavancin appears to correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) based on animal models of infection.

Exposure-response analyses from both preclinical and clinical studies support the treatment of clinically relevant Gram-positive microorganisms (e.g. S. aureus and S. pyogenes) causative of ABSSSI with a single 1,200 mg dose of ORBACTIV.

12.3 Pharmacokinetics

The population PK analysis was derived using data from the two Phase 3 ABSSSI clinical trials in 297 patients. The mean (±SD) pharmacokinetic parameters of oritavancin in patients following a single 1,200 mg dose are presented in Table 3.

Oritavancin exhibits linear pharmacokinetics at a dose up to 1,200 mg. The mean, population-predicted oritavancin concentration-time profile displays a multi-exponential decline with a long terminal plasma half-life.

12.4 Microbiology

ORBACTIV is a semi-synthetic, lipoglycopeptide antibacterial drug. ORBACTIV exerts a concentration-dependent bactericidal activity in vitro against S. aureus, S. pyogenes, and E. faecalis.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals have not been conducted to determine the carcinogenic potential of oritavancin.

No mutagenic or clastogenic potential of oritavancin was found in a battery of tests, including an Ames assay, in vitro chromosome aberration assay in Chinese hamster ovary cells, in vitro forward mutation assay in mouse lymphoma cells and an in vivo mouse micronucleus assay.

Oritavancin did not affect the fertility or reproductive performance of male rats (exposed to daily doses up to 30 mg/kg for at least 4 weeks) and female rats (exposed to daily doses up to 30 mg/kg for at least 2 weeks prior to mating). Those daily doses would be equivalent to a human dose of 300 mg, or 25% of clinical dose. Higher doses were not evaluated in nonclinical fertility studies.

14.1 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 1,200 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 4 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 5 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 6 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.

16.1 How Supplied/Storage

ORBACTIV is supplied as a sterile white to off-white lyophilized powder in single-dose clear glass vials containing 400 mg of oritavancin (NDC 70842-140-01), packaged in a carton of 3 vials (NDC 70842-140-03).

ORBACTIV vials should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP, Controlled Room Temperature (CRT)].

Allergic Reactions

Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should inform their healthcare provider about any previous hypersensitivity reactions to oritavancin products, other glycopeptides (vancomycin, telavancin, or dalbavancin) or other allergens.

Diarrhea

Patients should be advised that diarrhea is a common problem caused by antibacterial drugs including ORBACTIV, which usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider.

Development of Antibacterial Resistance

Patients should be counseled that antibacterial drugs including ORBACTIV should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ORBACTIV is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ORBACTIV or other antibacterial drugs in the future.

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