Orbactiv Drug Information

Dosage and

Administration Overview There are two oritavancin products (ORBACTIV and KIMYRSA™, another oritavancin product) that: Are supplied in different dose strengths of oritavancin . Have different recommended durations of infusion. Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents . Carefully follow the recommended dosage and dose preparation instructions for ORBACTIV in this prescribing information (PI). Refer to the KIMYRSA prescribing information for relevant information of the other oritavancin product.

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 .

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. 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 the contents to avoid foaming and ensure that all ORBACTIV powder is completely dissolved to form a reconstituted solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Each reconstituted vial should appear to be a clear, colorless to pale yellow solution, free of visible particles. Dilution : Use ONLY 5% dextrose injection (D5W) for dilution to prepare the final intravenous solution for infusion. Do NOT use Sodium Chloride Injection for dilution as it is incompatible with ORBACTIV and may cause precipitation of the drug.

Since no preservative or bacteriostatic agent is present in ORBACTIV, aseptic technique must be used in preparing the final intravenous solution as follows: Withdraw and discard 120 mL from a 1000 mL intravenous bag of D5W. Withdraw 40 mL from each of the three reconstituted vials of ORBACTIV and add to D5W intravenous bag to bring the bag volume to 1000 mL. This yields a concentration of 1.2 mg/mL. Discard any unused portion of the reconstituted solution remaining in each vial. Storage and Use of 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.

Compatibility

ORBACTIV solution for administration by 3-hour infusion is ONLY compatible with: 5% dextrose injection (D5W)

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.

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. Table 1: Incidence of Selected Adverse Reactions Occurring in ≥1.5% of Patients Receiving ORBACTIV in the Pooled ABSSSI Clinical Trials Adverse Reactions ORBACTIV N=976 (%) Vancomycin N=983 (%) Gastrointestinal disorders Diarrhea 36 32 Nausea 97 103 Vomiting 45 46 Nervous system disorders Dizziness 26 26 Headache 69 66 General disorders and administration Infusion site phlebitis 24 15 Infusion site reaction 19 34 Infections and infestations Abscess (limb and subcutaneous) 37 23 Investigations Alanine aminotransferase increased 27 15 Aspartate aminotransferase increased 18 15 Cardiac disorders Tachycardia 24 11 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

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.

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 . 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 C max 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).

Drug-Laboratory Test Interactions Prolongation of Certain Laboratory Coagulation Tests

ORBACTIV may artificially prolong certain laboratory coagulation tests (see Table 2 ) by binding to and preventing the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests . For patients who require monitoring of anticoagulation effect within the indicated time after 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. ORBACTIV does not interfere with coagulation in vivo. In addition, ORBACTIV does not affect tests that are used for diagnosis of Heparin Induced Thrombocytopenia (HIT). Table 2: Coagulation Tests Affected and Unaffected by ORBACTIV Elevated by ORBACTIV Unaffected by ORBACTIV Prothrombin time (PT) up to 12 hours Chromogenic Factor Xa Assay International normalized ratio (INR) up to 12 hours Thrombin Time (TT) Activated partial thromboplastin time (aPTT) up to 120 hours Activated clotting time (ACT) up to 24 hours Silica clot time (SCT) up to 18 hours Dilute Russell's viper venom time (DRVVT) up to 72 hours D-dimer up to 72 hours Positive Indirect and Direct Antiglobulin Tests (IAT/DAT) Positive IAT/DAT were noted with administration of oritavancin products, including ORBACTIV, in studies with healthy volunteers and patients with ABSSSI. Positive IAT may interfere with cross-matching before blood transfusion .

Pregnancy Risk Summary There are no available data on ORBACTIV use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no effects on embryo-fetal development or survival were observed in pregnant rats or rabbits treated at the highest doses throughout organogenesis with intravenous oritavancin, at doses equivalent to 25% of the single clinical dose of 1,200 mg (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oritavancin at the highest doses administered throughout organogenesis, 30 mg/kg/day (gestation days 6-17) and 15 mg/kg/day (gestation days 7-19), respectively. Those doses would be equivalent to a human dose of 300 mg, or 25% of the single clinical dose of 1,200 mg.

Higher doses were not evaluated in nonclinical developmental and reproductive toxicology studies.

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

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.

Hypersensitivity

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

In the ORBACTIV clinical program there was no incidence of accidental overdose of ORBACTIV. Based on an in vitro hemodialysis study, ORBACTIV is unlikely to be removed from blood by hemodialysis. In the event of overdose, supportive measures should be taken.